Pseudogenes: Molecular Fossils or Functional Elements?

From: Josh Bembenek (jbembe@hotmail.com)
Date: Thu May 01 2003 - 11:44:14 EDT

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    Uh oh! Pseudogenes with a function! This discovery casts another doubt on
    our list of solid evolutionary "proofs." See the following commentary on a
    Nature article.

    Maybe genomes aren't simply littered wastelands of evolutionary byproducts,
    but are composed largely of important elements that contribute to the
    purposeful generation of organisms? Ridiculous idea, to be sure. I have
    always found arguments concerning the sloppiness of design in biology to be
    extremely inept for supporting evolution. If you have billions of years of
    evolutionary processes to work on refining something through random mutation
    and natural selection, waste should be eliminated not accrued. At the same
    time, it remains an open question as to how much function and purpose all
    elements of the genome have in terms of biological activity. But of course,
    for the adamant evolutionist, even if pseudogenes aren't molecular fossils,
    the function they retain simply shows us the creativity of evolutionary
    processes, right? Thus can any evidence negate/ bring question to the
    veracity of evolution? This article characterizes the whole scenario as a
    product of evolution despite the fact that the finding challenges the
    long-held belief that pseudogenes are waste products of evolution. Now they
    aren't necessarily waste, but we *know* that they are still byproducts of
    evolution. Provocative finding indeed!!

    Molecular biology: Complicity of gene and pseudogene

    JEANNIE T. LEE

    Jeannie T. Lee is at the Howard Hughes Medical Institute, Department of
    Molecular Biology, Massachusetts General Hospital, and the Department of
    Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA.
    e-mail: lee@molbio.mgh.harvard.edu

    'Pseudogenes' are produced from functional genes during evolution, and are
    thought to be simply molecular fossils. The unexpected discovery of a
    biological function for one pseudogene challenges that popular belief.

    Pseudogenes are defective copies of functional genes that have accumulated
    to an impressive number during mammalian evolution1. Dysfunctional in the
    sense that they cannot be used as a template for producing a protein,
    pseudogenes are in fact nearly as abundant as functional genes2, 3. Why have
    mammals allowed their accumulation on so large a scale? One proposed answer
    is that, although pseudogenes are often cast as evolutionary relics and a
    nuisance to genomic analysis, the processes by which they arise are needed
    to create whole gene families4, such as those involved in immunity and
    smell. But are pseudogenes themselves merely by-products of this process? Or
    do the apparent evolutionary pressures to retain them hint at some hidden
    biological function? For one particular pseudogene, the latter seems to be
    true: elsewhere in this issue (page 91), Hirotsune and colleagues5 report
    the unprecedented finding that the Makorin 1-p1 pseudogene performs a
    specific biological task.

    Hirotsune et al.5 had been analysing mice in which copies of a fruitfly gene
    called Sex-lethal were randomly inserted in the mouse genome. In the course
    of their studies, they encountered one mouse line that died shortly after
    birth from multi-organ failure. As this occurred in only one mouse line out
    of many, the results could not be explained by aberrant Sex-lethal
    expression. Instead, the authors attributed their finding to a disruption of
    the particular stretch of genomic information into which Sex-lethal had
    inserted in this case. Whereas some might have dismissed the line as an
    aberration and unworthy of the effort required to characterize it, Hirotsune
    and colleagues delved deeper and were rewarded with the surprising finding
    that a pseudogene can regulate the expression of the functional gene from
    which it arose.

    The authors first found that, in the mouse line in question, the inserted
    Sex-lethal gene disrupted Makorin1-p1 a pseudogene copy of the functional
    Makorin1 gene. Only recently identified6, Makorin1 is an ancient gene that
    has been evolutionarily conserved from nematode worms to fruitflies and
    mammals, and encodes a putative RNA-binding protein. It is the prototype of
    a large family of Makorin genes and pseudogenes, and is located on mouse
    chromosome 6.

    By contrast, Hirotsune et al. found that the pseudogene Makorin1-p1 lies on
    chromosome 5. Like the original gene, this pseudogene can be 'transcribed'
    into a messenger RNA copy. But it has incurred mutations during evolution,
    so the mRNA cannot, as is usual, be used to produce a protein. Further
    differences between the gene and pseudogene include the fact that the
    Makorin1-p1 mRNA contains only the first (that is, 5') 700 nucleotides of
    the Makorin1 mRNA. Moreover, whereas both copies (one from the mother and
    one from the father) of the Makorin1 gene can be transcribed, the
    Makorin1-p1 pseudogene is paternally 'imprinted', so that only the paternal
    copy is expressed.

    Normally, Makorin1 mRNA is expressed throughout the animal6. But Hirotsune
    et al. found that when the paternal Makorin1-p1 pseudogene was disrupted,
    the expression of Makorin1 was markedly reduced in embryos and throughout
    birth and weaning. This implies that the pseudogene is normally required for
    the high-level expression of Makorin1. Interestingly, of the two forms of
    Makorin1 mRNA, only the smaller 1.7-kilobase transcript was downregulated
    the larger 2.9-kilobase copy was unaffected. The long and short forms are
    identical except in a region at the so-called 3' end that is not translated
    into protein. So, it seems that this region in the long form functions
    independently to keep expression levels high.

    The authors also wondered whether the imprinting of Makorin1-p1 is
    mechanistically central to Makorin1 expression. However, its disruption had
    equal effects on both maternal and paternal Makorin1 genes. So it seems that
    the imprinting of Makorin1-p1 is an odd happenstance that has little or
    nothing to do with its function. Rather, it seems likely that, when
    Makorin1-p1 arose, it fortuitously integrated into a chromosomal region that
    was already imprinted.

    This study5 generates many new and exciting questions. For instance, is
    Makorin1-p1 the only Makorin pseudogene that regulates Makorin1? Considering
    that disruption of Makorin1-p1 causes only a partial loss of expression of
    the functional gene, one might speculate that there are indeed other
    pseudogenes whose functions partly overlap, and that the deployment of an
    entire pseudogene battalion might be a feasible strategy of gene regulation.

    Furthermore, how does Makorin1-p1 regulate Makorin1? The authors found that
    the 700-nucleotide 5' region of Makorin1-p1 not only was required but was
    also sufficient for regulation in experiments in vitro. These experiments
    also suggested that the pseudogene acts sequence-specifically, affecting
    only those genes that show some sequence similarity to itself.

    Non-protein-coding RNAs have recently been shown to perform a variety of
    tasks, such as gene silencing, catalysis and the regulation of development7.
    So Makorin1-p1's mechanism of action might involve its non-coding RNA
    product, rather than the pseudogene itself. Hirotsune et al. propose that
    this product works to stabilize the Makorin1 mRNA (Fig. 1a). They favour a
    model in which the first 700 nucleotides of the Makorin1 mRNA contain a
    recognition site for a destabilization factor. Because this 700-nucleotide
    domain is shared by the Makorin1-p1 mRNA, the expression of the pseudogene
    would provide a means of titrating out the destabilizing factor through
    direct competition. In this model, the longer Makorin1 mRNA is unaffected
    because its 3' untranslated region protects it from degradation. An
    extension of this idea is that Makorin1 self-regulates: it has been
    suggested that it encodes an RNA-binding protein6, which might be the
    destabilizing factor that downregulates the short form of its own mRNA.

    Figure 1 Gene regulation by a pseudogene. Full legend

    High resolution image and legend (43k)

    Given the available data, however, another mechanism could be at work (Fig.
    1b). This is suggested by the fact that mRNA stability is usually controlled
    by elements in the 3' untranslated region8 rather than at the 5' end,
    where the key 700-nucleotide region of Makorin1 is found. The alternative
    mechanism would involve the pseudogene DNA locus directly. For example,
    perhaps the 700-nucleotide region in the gene and pseudogene contains
    elements that, on binding certain proteins, repress transcription. In this
    model the repressor proteins would be limited in availability, so that
    Makorin1-p1 would compete for repressor binding. These two models
    RNA-mediated versus DNA-mediated have mechanistic differences and could be
    tested.

    Whatever the underlying mechanism, the work of Hirotsune et al.5 is
    provocative for revealing the first biological function of any pseudogene.
    It challenges the popular belief that pseudogenes are simply molecular
    fossils the evidence of Mother Nature's experiments gone awry. Indeed, it
    suggests that evolutionary forces can work in both directions. The forward
    direction is driven by pressures to create new genes from existing ones, an
    imperfect process that often generates defective copies of the original. But
    these defective copies need not be evolutionary dead ends, because pressures
    in the reverse direction could modify them for specific tasks. In the case
    of Makorin1 and Makorin1-p1, the result of bidirectional selection is that
    one gene cannot exist without the other an example of functional
    complicity between a perfected product of evolution and its derivative
    castaway. Might the pseudogene copies of other functional genes be similarly
    useful?

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