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    X2: Uncannier Genetics
    By Josh Witten | May 27th 2009 06:15 PM | 4 comments | Print | E-mail | Track Comments
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    In March, we took a critically acclaimed critical look at the genetics of superpowers in the X-Men movie franchise.  In addition to Cath Ennis's recommendation that Nature put a hard-working rugbyologist on the payroll doing movie reviews, Karl Haro von Mogel1 from Biofortified was kind enough to include our effluvia in the 29th edition of Mendel's Garden.

    As you may or may not recall, when we last left the X-Men we had deduced that the X Gene mutations that cause the sine qua non mutant powers most likely increase expression2 of a transcription factor and that the beneficial mutant power effect sizes are exponentially distributed, like normal mutations in other, non-superpowered genes.  The paternal-only inheritance of mutant powers remained unresolved, leaving our suspension of disbelief broken into little pieces on the floor.

    Karl Haro von Mogel went above and beyond the call of duty by also suggesting a solution to this vexing problem: epigenetics.  Until recently, the last thing any self-respecting, mammalian geneticist wanted to think about was epigenetics.  Fortunately, Karl Haro von Mogel is a plant geneticist where epigenetics is that old, not quite trusted, friend responsible for most of your cool stories.  Having completed the Washington University 2009 Quad-Departmental Seminar Series focusing on epigenetics last week, the rugbyologist now feels ready to tackle the "epigenetic postulate".

    What is epigenetics?  How can epimutation cause paternal-only inheritance of mutant powers?  Are there other possible explanations?

    What is epigenetics?
    It really is a good question.  At one time, we actually knew an answer to that question.  The definition, in current usage, can be much harder to pin down.  Epigenetics now includes a diverese set of mechanisms outside DNA sequence that may affect the expression of phenotypic traits stably either across generations (i.e., meiotically stable) or cell divisions (i.e., mitotically stable).

    Being Old School, the rugbyologist prefers to use a more classic (classicker?) definition, which will also keep with Karl Haro von Mogel intent.  In this sense, epigenetics refers specifically to the transfer of information not encoded in the DNA sequence across generations.  This means that the information must survive transmission from the parents (through meiosis and fertilization) and development of the offspring (through mitosis).

    Imprinting is the most likely epigenetic mechanism to cause parental-only inheritance of mutant powers. 

    What is imprinting?
    What is imprinting?  Diploid babies receive a single copy of each and every non-sex chromosome from their parents, giving each baby two copies (i.e., diploid).  For some genes, however, expression of one only one copy is necessary or desirable.  In these cases, cells mothball one copy.  In some cases, the mothballing is random.  In others, the mothballing is directed at either the maternally or paternally inherited copy of the gene.  This directed shut down is called imprinting.     

    How would it work?
    How could imprinting cause paternal-only inheritance of mutant powers?  Let's start with the assumption that the X Gene copy inherited from one's mother, regardless of whether it is the normal allele or a power causing mutant allele, is shut down.  This means that the phenotypic effect of the X Gene is entirely determined by the copy inherited from one's father.  If your father has no mutant versions of the X Gene, then you will not have mutant powers, regardless of your mother's status.  If your father has two mutant copies, you are guaranteed to have a mutant power (I'm personally hoping for control of gravity).  If your father has one mutant copy and one normal copy, you have a 50% chance of having a mutant power.

    This mechanism would explain the phenotypes observed in Iceman's family (Figure 1).  Iceman's father could have inherited a mutant power inducing allele of the X Gene from paternal grandma Iceman, which would be shut down, and a normal version from paternal grandpa Iceman.  As a result, Iceman and his siblings would have a 50% chance of being "normal" and a 50% chance of having a mutant power (remember the X Gene version inherited from the mother does not contribute to the phenotype.

    Figure 1: Hypothetical three generation pedigree of Iceman's family (square=male, circle=female, black=normal, red=mutant power).  Internal rectangles indicate the two copies of the X Gene (black=normal version, red=mutant version) with grey overlay indicating imprinting shut down of maternally inherited copy.  First generation (top) represents Iceman's parents, neither or whom exhibit a mutant power.  Mother is assumed to be homozygous (3&4) for the normal version of the X Gene and father is assumed to be heterozygous (1&2).  Iceman inherits a mutant version from his father (2) and a normal version from his mother, which is shut down (4).  Iceman's brother, who also exhibited no mutant powers other than being a little bigoted ass, inherits normal versions from both parents (1 & 3).  Assuming that Rogue and Iceman figured out how to copulate successfully, their children (bottom) would have a 50% chance of having a mutant power and a 75% chance of carrying at least one copy of the mutant version of the X Gene.

    Parent specific imprinting has two other major advantages for movie science.  First, we do not yet understand the mechanisms controlling this phenomenon, which makes it harder for movie writers to screw up.  Second, it might also explain how lycanthropy sometimes "skips a generation" in the Michael J. Fox classic Teen Wolf.

    NOTES
    1: Yes, I am going to use the full name every single time in this article, because Karl Haro von Mogel is fabulous human nomenclature.
    2: With apologies to Jerry Coyne.
    3: If you are interested in the science of comic books, be sure to check out Ecocomics, the blog of comic book economics.

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    Comments

    logicman
    the rugbyologist prefers to use a more classic (classicker?) definition
    The English language has a surfeit of terms and affixes from the Greek, Latin and French.
    I think it's time we acknowledged the languages of other nations.

    I vote for 'classimas' - ( class + mas, Sp: 'more' ) - because it sounds Japanese.

    "The Rugbyologist is so classimas."

    Note:
    The expression "Merry Classimas Mr. Lawrence." is deprecated,
    and the 'Classima' trademark owner says: "Watch it, buster!"
    The structural complexity of the epigenetic control system of the organism is presented at www.misaha.com.
    The problem is that current physics has no idea about the physical carries of this system (biofield).

    Josh -

    Came across this column on twitter (I'm @genomicslawyer if you're on there) and had a very heavy small-world feeling when I saw the byline. Great piece, and glad to know that you're working in this field (and still playing rugby).

    Re: the mechanism of epigenetic inheritance, couldn't environmental changes play a role (e.g., by causing differences in DNA methylation which leads to different gene expression)? Wouldn't be a systematic/predictable as imprinting (which was a new concept to me) though.

    Drop me an email if you have a chance; would like to catch up.

    - Dan

    jtwitten
    Dan,

    Great to here from you.  You know those Duke rugby players are everywhere.

    Random effects could play a role, but building on my previous article on X-Men genetics, I was focused on dealing with the heritable issues of mutant powers.  The evidence is not convincing that DNA methylation is heritable in a non-sequence dependent way.  In my "expert" opinion, the non-sequence determined effects of epigenetics are grossly over-estimated based on the current data.