‘A novel is a great way to learn genetics’: A scene-based look at The Sirens, Middlesex and The Covenant of Water

I love when fiction unfurls a compelling tale whose protagonist has an ultrarare genetic disease.

My most recent favorite is The Sirens. 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.

But before The Sirens came Middlesex and The Covenant of Water. Each elaborates a complex plot around an unusual condition caused by mutation in a single gene. And all three present solid science – a story is a great way to learn genetics.

In MiddleSex She Becomes He
The classic tale based on a single-gene condition is Middlesex, by Jeffrey Eugenides, a Pulitzer Prize winner published in 2002.

Protagonist Calliope Stephanides is raised as a girl, although her genitalia are ambiguous – a small penis or large clitoris? But as a teen, she knows she is male, and modifies her name accordingly.

Cal inherited 5-alpha reductase deficiency/ (5-αRD). 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’t making testosterone.

But Cal is biologically male, with a defining Y chromosome and functioning SRY gene, which determines maleness. She has testes, and inside, her reproductive tract is male. But the outside didn’t get the message, and appears more female.

Cal can’t make 5-αRD – until puberty. Then, the adrenal glands, atop the kidneys, start to produce testosterone. And Cal’s voice deepens, facial hair sprouts, and muscles enlarge. Breasts don’t grow and menstruation doesn’t begin, while the clitoris extends into a penis. Cal makes sperm – and feels male.

In Middlesex, Cal is the consequence of incest between his grandparents, who were brother and sister and confined together during the Armenian genocide. 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.

Sometimes sexual identity isn’t as simple as XX or XY, vagina or penis. (Perhaps politicians should learn some biology.)

The Dominican Republic had a highly open-minded approach to 5-αRD, which was more prevalent than elsewhere due to consanguinity (blood relatives having children together).

In the 1970s, 22 young girls reached the age of puberty and began to manifest signs of maleness – prominent muscles, deepening voice, an extending clitoris and surrounding skin. These special teens were given their own gender name—guevedoces, for “penis at age 12.” The condition is also more prevalent in Papua New Guinea, Turkey, and Egypt – it is exceedingly rare elsewhere.

“To 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,” according to a Goodreads review. I agree.

The Covenant of Water and a Question of Balance
My second favorite novel built around a single-gene disorder is The 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 DNA Science.

The tale traces the bad luck of members of three generations of a family in Kerala, India, from 1900 to 1977.
“The family … suffers a peculiar affliction: in every generation, at least one person dies by drowning – and in Kerala, water is everywhere,” reads the jacket cover.

Were the drownings repeated bad luck, or a familial recklessness? “The Condition” 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.

An old pedigree drawing, hidden for generations, depicted affected family members. It included only males, afflicted females deemed only to exhibit “eccentricities”- 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.

The highly inbred family passed on that odd trait from a long-ago group of founders.

A contemporary character with medical training assembles the puzzle pieces and zeroes in on the family’s 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.

To weave a three-generation saga from the symptoms of a rare syndrome is brilliant. Yet the genetic condition behind The Sirens is perhaps even more so.

The Sirens Mimic Mermaids
Middlesex is from 2002, The Covenant of Water from 2023, The Sirens, 2025.

The two pairs of sisters in the dual timeline of The Sirens are linked by strange symptoms: skin that turns translucent, greenish-blue, and shimmering with tiny scales upon exposure to water, with webbed hands and feet – picture mermaid Daryl Hannah in the 1984 film Splash. The four women also sleepwalk during intense dreams that connect them across time.

In the dual timeline, Jess and Lucy, 18 years apart, are contemporary, events occurring in 2019. Twins Mary and Eliza’s story takes place in 1800.

(SPOILER: Anyone who’s ever watched a soap opera or read a novel knows that a generational age difference between supposed siblings signifies not a surprise “change-of-life” baby, but a teen mom pretending to be an older sis. But the “surprise,” which surfaces far into the book, explains the genetic basis of the odd manifestations. The long-ago twins as well as Jess’s mother all had the mermaid trait.)

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’s 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.

In the present, in the same remote region where the ship crashed, Lucy and Jess dream intensely of Mary and Eliza’s ordeal. All four have the odd skin affliction.

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’ character uncontrollably sculpting model mountains from mashed potatoes after witnessing a UFO near the Devils Tower monument in Wyoming, in the film “Close Encounters of the Third Kind.”

But, like in Middlesex and The Covenant of Water, biology offers an explanation.

The sister pairs have aquagenic urticaria – their skin reddens and roughens upon exposure to water, with the webbed hands and feet thrown in. And like 5-αRD and vestibular schwannomatosis, the condition is real.

A 1964 report in JAMA describes “contact sensitivity reaction to water.” The skin webbing is syndactyly, part of several genetic syndromes.

More interesting than the amorphous phenotype of the time-traveling part-time mermaids is the idea of genetic memory. How can Lucy and Jess be so aware of the twins, feel their anguish and misery and desperation?

Epigenetics may explain the phenomenon.

Instead of similarities based on inheriting shared gene variants, the modern sisters have inherited patterns of gene expression that ebb at each generation.

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 “imprint” can pass from generation to generation, weakening with each transfer, without changing the underlying DNA sequence.

Perhaps I’m reading too much science into these amazing works of fiction. But I can’t help myself, that’s what scientists do – 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.

Ricki Lewis is a science writer with a PhD in genetics. Check out Ricki’s website

A version of this article was originally posted at PLOS Blog and has been reposted here with permission. Any reposting should credit the original author and provide links to both the GLP and the original article. Find PLOS Blog on @plos