July182012

I sent this paper to JK Rowling explaining how the wizarding gene could be singular, autosomal, and dominant despite the protests of a bunch of fans who stopped learning genetics after Punnett squares. Warning: Contains science

Mrs. Rowling,

I read your statement that the wizarding gene is dominant.  I have heard criticism that this does not explain muggle-borns, squibs, or the steady inheritance pattern of magical abilities; but I got your back.  Magical ability could be explained by a single autosomal dominant gene if it is caused by an expansion of trinucleotide repeats with non-Mendelian ratios of inheritance.

As we all know, DNA is made up of the nucleotide bases guanine, cytosine, adenine, and thymine.  The sequences of these bases determine what products are transcribed.  Trinucleotide repeats are one such possible sequence.  Huntington’s disease is a well-known genetic condition.  The Huntington’s Disease Collaborative Research Group (1993) proved that the disease was caused by CAG (cytosine-adenine-guanine) trinucleotide repeats.  The Huntington gene is dominant and autosomal (not linked to sex chromosomes).   Normally, a person has 11 to 34 CAG repeats in the gene of interest, which causes the transcription of the normal huntingtin protein.  Unfortunately, when an individual has 42 to over 66 CAG repeats, the abnormal huntingtin protein transcribed causes serious symptoms later in life.  The huntingtin gene with an abnormal number of repeats shows dominant patterns of inheritance over the huntingtin gene containing a normal number of repeats.  Let us postulate that the gene determining magical ability contains trinucleotide repeats.

Trinucleotide repeats are inherently unstable, so DNA replication errors, such as slippage, are more likely to occur.  The repeat sequence can become longer over succeeding generations because these sequences are often susceptible to genetic expansion, a type of mutation which increases the number of repeats.  The phenotypic effects of trinucleotide expansions can be predicted by a certain threshold amount of repeats.  With the huntingtin gene, some individuals can have an abnormally high amount of repeats but still be phenotypically normal.  As long as there are less than 42 repeats, the individual is usually healthy.  If 100 repeats are necessary for the gene to be of the magical dominant allele variety, the recessive non-magical, or muggle, allele type might only contain about 50 repeats.  So, within a range, most muggles have about 50 trinucleotide repeats, but like any other trait there will be variation and some muggles might have 90 repeats and still be phenotypically non-magical.  Muggle-borns are caused by spontaneous mutations.  When investigating two instances of spontaneous mutation causing Huntington’s disease, the Huntington’s Disease Collaborative Research Group found evidence that the parental DNA was on the extreme high end of the phenotypically normal range, with 33 or 36 repeats.  Therefore, a muggle with about 90 repeats could, through genetic expansion, produce a child with at least 100 repeats (muggle-born witch/wizard).  Though the muggle would still be more likely to produce a non-magical child, he or she would have better odds of breaking the 100 repeat threshold than two muggles with the usual 50 repeats.  This implies that the 90 repeat muggle would also be more likely to have a recurrence than two random muggles mating, which might explain the Creevey brothers.  Looking at the global picture, such rarities are bound to happen sometimes.  But on the individual basis, the more likely cause of such a case would be false paternity.

There would be two genetic explanations for squibs.  Either the individual did not inherit the wizarding gene despite TRD (explained in the next paragraph) or the individual has a rare deletion mutation removing a series of trinucleotide repeats.  The latter cause provides an explanation for occasional resurfacing of the magical phenotype in the children of squibs.  It is unlikely that enough repeats would be removed to keep them far from the 100 repeat threshold required for magical abilities.  Over the generations, trinucleotide expansion could push the progeny over the 100 repeat threshold.  Note, however, that the squib would be no more likely to produce magical children than a muggle with an equal number of repeats.  Despite their different heritages, their mutations make them genetically similar.  This suggests that their limited ability to interact with the magical world (seeing Hogwarts and dementors) might be environmentally influenced, rather than genetic.  Cross muggle-wizard adoption studies could provide evidence for this hypothesis.  If wizard-raised muggles have the same limited abilities or muggle-raised squibs fail to develop these abilities it would prove an environmental factor.  If the adoption studies provide no evidence, we must remember that these studies would not account for environmental factors in the womb.  Unless there are any case studies of gestational surrogacy with a muggle child and a witch mother, the data would be inconclusive.

Most witches and wizards would be heterozygous for this magical gene, but clearly this does not impact the heritability of magical ability.  Mendelian patterns of inheritance would have you expect that two heterozygotes would produce only 3 out of 4 magical children.  A heterozygote and a muggle (homozygous recessive) would produce only 2 out of 4 magical children.  But this is not what is observed in wizarding pedigrees.  There are many reasons dominant and recessive genes might not show the expected Mendelian ratios of inheritance.  Punnett squares show classic Mendelian inheritance well, but this straightforward inheritance pattern does not always apply.  Even if gametes (sex cells) are arranged to this ratio after genetic recombination, all gametes are not necessarily equally likely to fertilize or be fertilized.  Transmission ratio distortion (TRD) is the preferred inheritance of one particular parental allele.  TRD can be caused by a variety of mechanisms.  Koide et al. (2008), while studying the matter in plants, summarized that, “the nonrandom segregation of chromosomes during meiosis (Pardo-Manuel de Villena and Sapienza 2001; Birchler et al. 2003; Fishman and Willis 2005), preferential dysfunction of gametes in hybrids (Lyttle 1991; Teminet al. 1991; Silver 1993; Moyle and Graham 2006;U´ beda and Haig 2005), and preferential success of gametes in fertilization (Price 1997; Diaz and MacNair 1999)” are all possible causes of non-Mendelian inheritance patterns.

Gametes are prone to certain functional errors because they are haploid cells which only contain half the DNA as other human cells.  Martin-DeLeon et al. (2005) found evidence for their Lack of Sharing Hypothesis which explained TRD caused by abnormal mammalian sperm development.  Normally, spermatocytes are connected by cytoplasmic bridges and gene products are shared.  This allows all male gametes to develop identically together despite their individually incomplete and unique genomes.  When there is a lack of sharing, the sperm will not be developed properly and will be much less likely to successfully fertilize an egg.  If a certain gene affects these cytoplasmic bridges, the inheritance ratios will also be affected.  Not much has been conclusively proven in humans, particularly concerning how TRD applies to oocytes, or female gametes.  This is understandable, since the development of oocytes could only be observed in a female fetus.  Exactly why the wizarding gene is so penetrant may forever remain a mystery, but there are rational scientific explanations for preferred inheritance of one parental allele over another.  Close scrutiny of wizarding pedigrees, particularly in families with many muggle marriages may help explain the mechanism.

That is all for defending your statement, Mrs. Rowling.  But I have two more possible implications if you will humor me.  Sometimes in succeeding generations, the number of trinucleotide repeats, which was already past the threshold, can become extreme and cause a more pronounced phenotype.  This phenomenon is called genetic anticipation.  There may be a genetic explanation for the variation of power among witches and wizards.  Huntington’s disease symptoms are likely to be more severe with an earlier onset if the huntingtin gene contains a number of repeats significantly higher than the required threshold.  Just like among muggles, the wizarding community would have variation in the number of trinucleotide repeats.  Clearly, some witches and wizards are stronger than others, and it should not seem absurd to suggest that there are probably some genetic factors which contribute to this phenomenon, similar to the genetic factors of athletic ability.  Possibly, a greater number of repeats corresponds with greater magical ability, but proving this would require rigorous statistical analysis which controlled for confounding variables.

When considering evolutionary history, Occam’s razor is often incorporated.  The evolutionary biologist must consider the simplest way an organism or trait could evolve, because that is almost always how evolution works.  Regardless of the genetic cause, it makes the most sense that all magical ability resulted from mutations to muggle DNA.  If a spontaneous mutation is commonly able to produce heritable magical ability in a child today, why would a more complicated method be needed to explain the beginning of wizarding genealogies?  The first “pure-blood” wizards must have been muggle-borns whose muggle heritage would be forgotten by subsequent generations.  This logical deduction obviously has a few implications for modern wizarding genealogical thought.  Any classification of pure-blood, half-blood, or other mixes is illogical.  What are commonly known as muggle-borns would be better classified as a witch or wizard recently derived from muggles.  Muggle-borns should simply be considered new wizarding lines just starting out.  By the same token, squibs can be viewed as a return to the ancestral phenotype, which might be termed devolution.  (Evolutionary biologists hate that word because it implies that evolution is goal-oriented towards increased complexity.)  On the other hand, if my previous speculation about excessive trinucleotide expansions causing greater magical ability is correct, then these old wizarding families can accurately pride themselves in their unique genetics, since further trinucleotide expansions have likely occurred over many generations.  Any increase in magical power down the line would be an example of genetic anticipation.

Sorry this is late.  I was not a biology major when I started reading Harry Potter in third grade.  I think your Harry Potter encyclopedia should include a section better explaining the genetics of magical abilities.  These are my hypotheses about wizarding genetics, and if you do not like them there are probably plenty other ideas out there.  All of your original fans are grown up now and I am sure the ones who became geneticists would gladly give you their input.


Much love,
Andrea Klenotiz

 

PS.  Please sign the enclosed picture so I can frame it and tell everyone the story of how I sent JK Rowling a six page scientific paper about wizarding genetics.

 

 

 

 

Bibliography

Birchler, J. A., R. K. Dawe and J. F. Doebley, (2003) Marcus Rhoades,  Preferential segregation and meiotic drive. Genetics 164: 835–841.

Diaz, A., and M. R. MacNair, (1999) Pollen tube competitions as a mechanism of prezygotic reproductive isolation between Mimu-lus nasutus and its presumed progenitor M. guttatus. New Phytol. 144: 471–478.

Fishman, L., and J. H. Willis, (2005) A novel meiotic drive locus almost completely distorts segregation in Mimulus (monkeyflower) hybrids. Genetics 169: 347–353.

The Huntington’s Disease Collaborative Research Group (1993): A Novel Gene containing a Trinucleotide Repeat that is Expanded and Unstable on Huntington’s disease chromosomes. Cell 72: 971-983.

Martin-DeLeon, P. A., Zhang, H. Carlos R. Morales, Yutong Zhao, Michelle Rulon, Barry L. Barnoski, Hong Chen, Deni S. Galileo: Spam1-Associated Transmission Ratio Distortion in mice: elucidating the mechanism. Reprod. Biol Endocrinol. 3: 32 (10 Aug 2005).

Koide, Y., K. Onishi, A. Kanazawa and Y. Sano. (2008) Genetics of speciation in rice, pp. 247–  259 in Rice Biology in the Genomics Era, edited by H. Y. Hirano, A. Hirai, Y. Sano and T. Sasaki.

Koide et al.  (2008)  The Evolution of Sex-Independent Transmission Ratio Distortion Involving Multiple Allelic Interactions at a Single Locus in Rice.  The Genetics Society of America 409-420

Lyttle, T. W.  (1991) Segregation distorters. Annu. Rev. Genet. 25: 511–557.

Moyle, L. C., and E. B. Graham.  (2006) Genome-wide association between hybrid sterility QTL and marker transmission ratio distortion. Mol. Biol. Evol. 23: 973–980.

Pardo-Manuel de Villena, F., and C. Sapienza.  (2001) Nonrandom segregation during meiosis: the unfairness of females. Mamm. Genome 12: 331–339.

Price, C. S. C.  (1997) Conspecific sperm precedence in Drosophila. Nature 388: 663–666.

Rowling, J.K. Harry Potter series. (1997-2007)  New York. Scholastic Books.

Silver, L. M.  (1993) The peculiar journey of a selfish chromosome: mouse t haplotypes and meiotic drive. Trends Genet. 9: 250–254.

Temin, R. G., B. Ganetzky, P. A. Powers, T.W. Lyttle, S. Pimpinelli et al.  (1991) Segregation distortion in Drosophila melanogaster: genetic and molecular analyses. Am. Nat. 137:    287–331.

U´beda, F., and D. Haig.  (2005) On the evolutionary stability of Mendelian segregation. Genetics 170: 1345–1357.

 

 

© Andrea Klenotiz, 2012

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