I love when fiction unfurls a compelling tale whose protagonist has an ultrarare genetic disease.<\/p>\n
My most recent favorite is\u00a0The Sirens<\/a>. Author Emilia Hart weaves a powerful tale of genetic memory manifest in two pairs of sisters, one aboard a doomed ship transporting women convicts from England to New South Wales circa 1780, the other contemporary.<\/p>\n But before\u00a0The Sirens\u00a0came\u00a0Middlesex<\/a>\u00a0and\u00a0The Covenant of Water<\/a>. Each elaborates a complex plot around an unusual condition caused by mutation in a single gene. And all three present solid science \u2013 a story is a great way to learn genetics.<\/p>\n In MiddleSex She Becomes He Protagonist Calliope Stephanides is raised as a girl, although her genitalia are ambiguous \u2013 a small penis or large clitoris? But as a teen, she knows she is male, and modifies her name accordingly.<\/p>\n Cal inherited\u00a05-alpha reductase deficiency\/<\/a>\u00a0(5-\u03b1RD). A missing enzyme keeps her cells from responding to testosterone, and reacting it into dihydrotestosterone (DHT), which is essential for a penis to develop. Cal looks like a she before puberty because her body isn\u2019t making testosterone.<\/p>\n But Cal is biologically male, with a defining Y chromosome and functioning\u00a0SRY\u00a0gene, which determines maleness. She has testes, and inside, her reproductive tract is male. But the outside didn\u2019t get the message, and appears more female.<\/p>\n Cal can\u2019t make 5-\u03b1RD \u2013 until puberty. Then, the adrenal glands, atop the kidneys, start to produce testosterone. And Cal\u2019s voice deepens, facial hair sprouts, and muscles enlarge. Breasts don\u2019t grow and menstruation doesn\u2019t begin, while the clitoris extends into a penis. Cal makes sperm \u2013 and feels male.<\/p>\n In\u00a0Middlesex, Cal is the consequence of incest between his grandparents, who were brother and sister and confined together during the\u00a0Armenian genocide<\/a>. From 1915 through 1917, the Ottoman government killed more than a million Armenians. Forced into long-term isolation, the grandparents turned to each other for comfort. And each passed along a recessive gene mutation; Cal inherited one copy from each.<\/p>\n Sometimes sexual identity isn\u2019t as simple as XX or XY, vagina or penis. (Perhaps politicians should learn some biology.)<\/p>\n The Dominican Republic had a highly open-minded approach to 5-\u03b1RD, which was more prevalent than elsewhere due to consanguinity (blood relatives having children together).<\/p>\n In the 1970s, 22 young girls reached the age of puberty and began to manifest signs of maleness \u2013 prominent muscles, deepening voice, an extending clitoris and surrounding skin. These special teens were given their own gender name\u2014guevedoces, for \u201cpenis at age 12.\u201d The condition is also more prevalent in Papua New Guinea, Turkey, and Egypt \u2013 it is exceedingly rare elsewhere.<\/p>\n \u201cTo understand why Calliope is not like other girls, she has to uncover a guilty family secret, and the astonishing genetic history that turns Callie into Cal, one of the most audacious and wondrous narrators in contemporary fiction. Lyrical and thrilling, Middlesex is an exhilarating reinvention of the American epic,\u201d according to a Goodreads review. I agree.<\/p>\n The Covenant of Water and a Question of Balance The tale traces the bad luck of members of three generations of a family in Kerala, India, from 1900 to 1977. Were the drownings repeated bad luck, or a familial recklessness? \u201cThe Condition\u201d often begins with panic in the presence of water, be it a bathtub, a river, a ditch, or merely falling headfirst into a puddle and passing out.<\/p>\n An old pedigree drawing, hidden for generations, depicted affected family members. It included only males, afflicted females deemed only to exhibit \u201ceccentricities\u201d- climbing trees, speaking their minds, hysteria in the bathtub, and avoiding water. Their headaches, dizziness, and facial weakness hid in plain sight for generations because of expectations of female docility.<\/p>\n The highly inbred family passed on that odd trait from a long-ago group of founders.<\/p>\n A contemporary character with medical training assembles the puzzle pieces and zeroes in on the family\u2019s plight: vestibular schwannomatosis, once called neurofibromatosis type 2. Benign tumors ensheathe the acoustic nerves in the inner ear with a bubble-wrap-like coating. And that impairs balance, hearing, and deforms facial features. It strikes 1 in 60,000 people.<\/p>\n To weave a three-generation saga from the symptoms of a rare syndrome is brilliant. Yet the genetic condition behind\u00a0The Sirens\u00a0is perhaps even more so.<\/p>\n The Sirens Mimic Mermaids The two pairs of sisters in the dual timeline of\u00a0The Sirens\u00a0are linked by strange symptoms: skin that turns translucent, greenish-blue, and shimmering with tiny scales upon exposure to water, with webbed hands and feet \u2013 picture mermaid Daryl Hannah in the 1984 film\u00a0Splash. The four women also sleepwalk during intense dreams that connect them across time.<\/p>\n In the dual timeline, Jess and Lucy, 18 years apart, are contemporary, events occurring in 2019. Twins Mary and Eliza\u2019s story takes place in 1800.<\/p>\n (SPOILER: Anyone who\u2019s ever watched a soap opera or read a novel knows that a generational age difference between supposed siblings signifies not a surprise \u201cchange-of-life\u201d baby, but a teen mom pretending to be an older sis. But the \u201csurprise,\u201d which surfaces far into the book, explains the genetic basis of the odd manifestations. The long-ago twins as well as Jess\u2019s mother all had the mermaid trait.)<\/p>\n The book opens with a Historical Note that sets the stage: the shipping of convicts from England to the colonies that became Australia, beginning in 1787. Mary and Eliza had been convicted of defending themselves from a male attacker and forced into the horror of the ship\u2019s belly with 60 other women and girls, for months. When the ship smashes into a cliff and shatters, the shape-shifting twins easily swim through an aperture and escape, like Clark Kent becoming Superman. Everyone else drowns.<\/p>\n In the present, in the same remote region where the ship crashed, Lucy and Jess dream intensely of Mary and Eliza\u2019s ordeal. All four have the odd skin affliction.<\/p>\n Jess is a painter whose eerie renderings of mermaids mirror the horrific past of her ancestors. Her compulsion to paint huge portraits is reminiscent of Richard Dreyfuss\u2019 character uncontrollably sculpting model mountains from mashed potatoes after witnessing a UFO near the Devils Tower monument in Wyoming, in the film \u201cClose Encounters of the Third Kind.\u201d<\/p>\n But, like in\u00a0Middlesex\u00a0and\u00a0The Covenant of Water, biology offers an explanation.<\/p>\n The sister pairs have\u00a0aquagenic urticaria\u00a0\u2013 their skin reddens and roughens upon exposure to water, with the webbed hands and feet thrown in. And like 5-\u03b1RD and vestibular schwannomatosis, the condition is real.<\/p>\n A 1964 report in\u00a0JAMA<\/a>\u00a0describes\u00a0\u201ccontact sensitivity reaction to water.\u201d\u00a0The skin webbing is\u00a0syndactyly, part of several genetic syndromes.<\/p>\n More interesting than the amorphous phenotype of the time-traveling part-time mermaids is the idea of\u00a0genetic memory. How can Lucy and Jess be so aware of the twins, feel their anguish and misery and desperation?<\/p>\n Epigenetics\u00a0may explain the phenomenon.<\/p>\n Instead of similarities based on inheriting shared gene\u00a0variants, the modern sisters have inherited patterns of gene\u00a0expression\u00a0that ebb at each generation.<\/p>\n Such epigenetic memory is due not to a sequence of DNA building blocks, but to the pattern of placement of methyl (CH3, or a carbon atom bonded to 3 hydrogen atoms) groups along the DNA of a chromosome, at points where it untwists. An epigenetic \u201cimprint\u201d can pass from generation to generation, weakening with each transfer, without changing the underlying DNA sequence.<\/p>\n Perhaps I\u2019m reading too much science into these amazing works of fiction. But I can\u2019t help myself, that\u2019s what scientists do \u2013 we evaluate evidence in the search for explanations. I wish I had the imagination to incorporate my knowledge of genetics into telling tales like these three talented authors.<\/p>\n Ricki Lewis is a science writer with a PhD in genetics. Check out Ricki\u2019s\u00a0website<\/a><\/strong><\/p>\n A version of this article was originally posted at\u00a0PLOS Blog<\/a>\u00a0and has been reposted here with permission. Any reposting should credit the original author and provide links to both the GLP and the original article. 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The classic tale based on a single-gene condition is Middlesex, by Jeffrey Eugenides, a Pulitzer Prize winner published in 2002.<\/p>\n
My second favorite novel built around a single-gene disorder is\u00a0The Covenant of Water, by physician Abraham Verghese (who is soon to give the commencement speech at a beleaguered Harvard). I reviewed the book here at\u00a0DNA Science<\/a>.<\/p>\n
\u201cThe family \u2026 suffers a peculiar affliction: in every generation, at least one person dies by drowning \u2013 and in Kerala, water is everywhere,\u201d\u00a0reads the jacket cover.<\/p>\n
Middlesex\u00a0is from 2002,\u00a0The Covenant of Water\u00a0from 2023,\u00a0The Sirens, 2025.<\/p>\n