A Family’s Shared Defect Sheds Light on the Human Genome
By NATALIE ANGIER JAN. 9, 2017
The mutations affect a newly discovered design feature of the DNA molecule called topologically associating domains, or TADs. It turns out that the vast informational expanse of the genome is divvied up into a series of manageable, parochial and law-abiding neighborhoods with strict nucleic partitions between them — each one a TAD.
Breach a TAD barrier, and you end up with the molecular equivalent of that famous final scene in Mel Brooks’s comedy, “Blazing Saddles,” when the cowboy actors from one movie set burst through a wall and onto the rehearsal stage of a campy Fred Astaire-style musical. Soon fists, top hats and cream pies are flying.
Dom DeLuise’s line about the chorus boys saying “Yessssssssssss” is like “steam escaping” is part of Mel Brooks’ long-running noticing that male homosexuals often have a hissy “s” lisssssp sound, the opposite of the very hetero Daffy Duck’s lithp sound.
Daffy’s accent was based on producer Leon Schlesinger, who used to offer the animators helpful advice such as, “Put in lotth of joketh, boyth, joketh are funny!”
When they debuted Daffy’s new voice for Schlesinger, they were worried that he’d get mad at them for mocking his speech impediment. But instead he enthused, “Jethuth Critht, thatth a funny acthent! Where’d you get that acthent?” (Or at least that’s Chuck Jones version. Mel Blanc’s version is somewhat different. Over many years of repeating these kind of Hollywood anecdotes, I’ve found, much to my surprise, that the world’s best joke tellers tended to improve their stories in the retelling.)
But with Singin’ in the Rain back in the news (here’s Mark Steyn on the death of Debbie Reynolds), I’m starting to think that there is a lot of Gene Kelly in Daffy Duck.
When I was a teenager in the 1970s, Gene Kelly was on TV all the time. If the weather was bad in Beverly Hills, the local TV news truck would drive over to Gene Kelly’s house and he’d come out on the lawn and give his comments on the weather. One thing I noticed was that Kelly had a huge ego: amour propre. He was like a really successful Daffy Duck. Dignity, always dignity:
Daffy was like Gene Kelly if you didn’t like him because he was so cocky and could torment him by keeping him from getting the career breaks he deserved.
Anyway, back to DNA science:
… For much of the past 50 years, genetic research has focused on DNA as a kind of computer code, a sequence of genetic “letters” that inscribe instructions for piecing together amino acids into proteins, which in turn do the work of keeping us alive.So, integration is kind of like cancer is what you’re saying, Natalie?
… “We realized that in order to understand how genetic information is controlled, we had to figure out how DNA was folded in space,” said Bing Ren of the University of California, San Diego.
… Through chromosome conformation studies and related research, scientists have discovered the genome is organized into about 2,000 jurisdictions, and they are beginning to understand how these TADs operate.
As with city neighborhoods, TADs come in a range of sizes, from tiny walkable zones a few dozen DNA subunits long to TADs that sprawl over tens of thousands of bases and you’re better off taking the subway. TAD borders serve as folding instructions for DNA. “They’re like the dotted lines on a paper model kit,” Dr. Dekker said.
TAD boundaries also dictate the rules of genetic engagement. …
Because TADs can be quite large, the way the Upper West Side of Manhattan comprises an area of about 250 square blocks, a genetic enhancer located at the equivalent of, say, Lincoln Center on West 65th Street, can amplify the activity of a gene positioned at the Cathedral of St. John the Divine, 45 blocks north.
But under normal circumstances, one thing an Upper West Side enhancer will not do is reach across town to twiddle genes residing on the Upper East Side.
“Genes and regulatory elements are like people,” Dr. Dekker said. “They care about and communicate with those in their own domain, and they ignore everything else.”
Scientists have learned that disruptions of the genome’s boundaries may cause syndactyly and other diseases, including some pediatric brain disorders that affect the brain’s white matter. …
The best evidence for the importance of TADs is to see what happens when they break down. Researchers have lately linked a number of disorders to a loss of boundaries between genomic domains, including cancers of the colon, esophagus, brain and blood.
In such cases, scientists have failed to find mutations in any of the protein-coding sequences commonly associated with the malignancies, but instead identified DNA damage that appeared to shuffle around or eliminate TAD boundaries. As a result, enhancers from neighboring estates suddenly had access to genes they were not meant to activate.
Reporting in the journal Science, Dr. Young and his colleagues described a case of leukemia in which a binding site for insulator proteins had been altered not far from a gene called TAL1, which if improperly activated is known to cause leukemia. In this instance, disruption of the nearby binding site, Dr. Young said, “broke up the neighborhood and allowed an outside enhancer to push TAL1 to the point of tumorigenesis,” the production of tumors.
Now that researchers know what to look for, he said, TAD disruptions may prove to be a common cause of cancer.
This Trump Era could be interesting if it encourages greater freedom of speech from fed-up old-timers like Angier.
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