I’ve been immersed in genetic genealogy, following up on a recent contact from a relative I didn’t know existed. While trying to imagine scenarios that might explain how we came to be connected, I contacted Ancestry.com for assistance in seeing actual data. When I found the obvious drop-down menus next to my matches on the website, I was astounded to recognize the unit used to assess the closeness of relationships – a centiMorgan.
I’m sure that’s Greek to most people. But to a former Drosophila (fruit fly) geneticist like me, “centiMorgan” (cM) brought an instant meaning: distance along a chromosome.
Invention of the centiMorgan is one of my favorite tales from the history of genetics. It provided the very first genetic map, and inspired the variations on the theme that were to come, including full genome sequencing.
The intuition that has sent millions of people googling centiMorgans, with more to come after all those DNA kits are opened and spat into for Christmas, goes back to a sleep-deprived 19-year-old with a fantastically brilliant idea, 105 years ago.
A Blast from the Past
Room 613 in Schermerhorn hall, at Columbia University in the early years of the twentieth century, was known as the “Fly Room.” At most hours of the day, because setting up fruit fly crosses and cataloging their traits requires collecting virgins according to the insects’ schedules, eight “fly pickers” sat, crammed at eight cluttered desks. There they sorted through etherized flies tallying their traits – red or white eyes, yellow or black bodies, full or notched wings.
Thomas Hunt Morgan was in charge, heading a new, experimental zoology program in the years just after the rediscovery of Gregor Mendel’s paper demonstrating inheritance patterns using pea plants. Could the fly pickers confirm that work, and maybe extend it? The noble Drosophila melanogaster, offering 30 generations a year and minimal requirements to happily breed, was the model organism of choice.
A 2014 film, The Fly Room, by Alexis Gambis, captures the atmosphere. My fruit fly love story, The Making of a Mutant, does the same from the point of view of a resident of a milk bottle fly colony. And here’s an excerpt from one of my books, Human Genetics: The Basics (Routledge Press, 2017, second edition):
“Every available surface was festooned with the small, cardboard-stoppered glass milk bottles, each housing hundreds of flies. Insect escapees would often light on the researchers’ hair, and the air bore the distinctive aroma of the overripe bananas mashed into milk bottle bottoms. Female flies would lay their eggs onto this goo, and out would hatch the first of three waves of larvae that would mature within it. The worm-like creatures with their perpetual motion jaws would eat themselves towards adulthood, finally encasing themselves in cocoons and, a few days later, emerging and unfolding as full-fledged flies. Half a dozen future Nobel laureates were among ‘Morgan’s boys,’ and the Fly Room spawned an academic pedigree of the founders of modern genetics in the twentieth century.”
To set up the experiments to trace traits, Morgan and the boys needed mutants. Making mutants using toxic chemicals and radiation hadn’t yet been invented, so the researchers waited for variants to arise spontaneously as the little beasts bred.
Gradually the young investigators accumulated a stable of intriguing flies and set up crosses to track inheritance patterns. Eventually, they discovered four groups of traits that tended to be passed together because, deduced Morgan, the genes that confer them are physically on the same chromosome. The fly has four types, in pairs. He envisioned genes linked on a chromosome but occasionally swapping positions, or “crossing over.”
Alfred Henry Sturtevant came to the Morgan lab as an eager young undergrad. In his own words, from his book “A History of Genetics”: “In 1909, the only time during his twenty-four years at Columbia, Morgan gave the opening lectures in the undergraduate course in beginning zoology. It so happened that C.B. Bridges (another famous geneticist) and I were both in the class. While genetics was not mentioned, we were both attracted to Morgan and were fortunate enough, though both still undergraduates, to be given desks in his laboratory the following year. The possibilities of the genetic study of Drosophila were then just beginning to be apparent; we were at the right place at the right time.”
As a child growing up on a farm in Alabama, Sturtevant had been intrigued with his father’s purebred horses, drawing and studying their traits using pedigree diagrams – excellent training for a future fruit fly geneticist.
In the Fly Room, Sturtevant set about figuring out which flies to cross to confirm and extend Mendel’s work in peas. He was intrigued by the occasional flies with trait combinations different from those of either parent, as if the genes on one copy of a chromosome had switched places with the corresponding genes on the other copy, before fertilization. That’s exactly what was happening.
As sperm or egg formed, the two chromosomes of a pair intertwined and crossed over, literally exchanging parts before separating, bearing new gene combinations. (It’s a little like people in different outfits exchanging pants and shoes.) Sturtevant kept score, and soon noted that the unexpected “recombinant” flies were rare compared to their brethren that resembled the parents.
Then he had the flash of genius: he saw how the experiments might reveal a relative map of gene positions on their chromosomes.
The First Genetic Map
Sturtevant considered six traits linked on the fly’s X chromosome, easy to study because the traits would show up in male offspring, with their lone Xs, without requiring further crosses. One night, he was struck with an idea so compelling that he cast his homework aside and stayed up until the wee hours, sketching.
What if the frequency of a recombinant class of offspring reflects relative distance of genes along a chromosome?
Genes at opposite ends of a chromosome would have a large recombinant class and represent a large physical distance, he predicted, but genes close together on the chromosome would generate few recombinants, simply because there was less space for a crossover to occur.
A shopping analogy may help to envision the mapping strategy. Imagine crossing a street to get to a store or restaurant. There are more places to cross along the 4.2 miles of the Las Vegas strip than along the few blocks of a Main Street in a small US town. The greater the distance, the more room for crossovers. Some of the ancestry testing websites use an exits-on-a-highway analogy (but that doesn’t capture crossing). More exits, longer distance.
At age 19, A. H. Sturtevant drew the first map depicting genes on a chromosome, published January 30, 1913 in The Journal of Experimental Zoology. Little did he know that his idea would become the foundation for all future genetic maps, and for people finding that they’re related using do-it-yourself DNA kits more than a century later.
From Joy to Jolt
Ancestry websites calculate the number of centiMorgans of DNA two people share at various sites among the 23 chromosome types. The extent of shared cMs matters, as does the number of sites. An important caveat is that certain stretches of chromosomes tend not to cross-over, and appear as extensive specific DNA sequences that are common within a population group that tends to reproduce among itself – like Jewish people of Ashkenazi descent. That is, a lot of us share stretches of DNA (see The Genomic Scars of Anti-Semitism). So two Jewish people discovering they are fifth or sixth cousins isn’t uncommon.
After my joy at recognizing the centiMorgans of fruit fly lore on the drop-down menus for my matches at Ancestry.com, listed in descending order, I felt a jolt. From the bottom up, I share 150-200 cM with a bunch of third cousins, 250-300 cM with a few potential second cousins, 690 cM with a known first cousin, yet 2000+ with my newfound relative! I uploaded my data to GEDMatch.com, and saw, again, that 2000+ cM person ahead of a very long list of increasingly distant cousins orders of magnitude behind in proximity.
It didn’t take a PhD in genetics to know what that meant.
To be continued …