Thanks to the unfounded predictions of Grampa Simpson, Lisa is convinced that she's genetically predisposed to lose her intelligence until Dr. Simpson reevaluates her. Meanwhile, Apu discovers Jasper Beardly frozen in his freezer, and turns the Kwik-E-Mart into a tourist's trap.
Lisa tries to solve a brain teaser, and she fails as Martin, Milhouse, Bart, and even Nelson can solve it. She does not remember the code combination for her school locker, also forgets to do an agriculture project, and does a last minute job of an "eraser pig", and loses her saxophone technique. These things point to evidence that Lisa fears she is losing her gift of intelligence. When she tells about this to Grampa, he tells her that all the members of the Simpson family—including himself, Homer, and Bart—started smart at first, but later became dumber, as part of the Simpson Genes. Eventually, Lisa becomes dumb like both Homer and Bart. After a nightmare of being married to Ralph and being unintelligent with children, she rejects her new-found idiocy.
Lisa appears on Smartline and demands that the citizens of Springfield treaure their brains. As she does this, Homer having found out what Abe has done, brings all of the Simpson family relatives to the house in an attempt to prove that the whole family is not a bunch of idiots. When all the Simpsons visit, Homer goes and asks all the men what their jobs are. These include running an unsuccessful shrimp company, shooting birds at the airport, dressing up like a millionaire and going to parties, jumping in front of cars and suing the drivers, begging celebrities for money, prison snitch and jug band manager. Lisa is more depressed and Homer sends all of them away, beginning to feel that the Simpsons are pathetic.
However as he does so, Marge points out that Homer only talked to the men in his family and asks him to talk to his female relatives. Homer reluctantly does so and he finds one in a white labcoat (and similar in appearance to Lisa) and asks what her career is--Homer reads her nametag as "Dr. Simpson," which perks Lisa up. Dr. Simpson reveals, "I'm the chief of complicated surgeries at an invasive care clinic." The rest of the women all reveal their careers as well, such as being an environmental lawyer, an architect and even the lead sales coordinator at a bed company, showing themselves to be very successful. When Lisa questions why the Simpson-gene didn't affect the women, Dr. Simpson reveals that the defective gene only exists on the Y chromosome, so only males are affected. With Lisa having a double-X chromosome, making her a female, she'll likely become very successful like the women on her father's side of the family. Lisa regains her confidence in being smart, knowing that the defective Simpson gene won't affect her due to her sex. However, Bart asks Homer that since Lisa and even Maggie are going to be successful if he will be an unintelligent failure like the men since he inherited the defective Simpson gene. He confirms it, making Bart wary and bemoaning his future as a failure. Homer reassures him that he will be a "spectacular failure". Bart happily accepts this and returns to playing with the other males with pans over their heads.
Lisa writes in her journal about how she feels like she can accomplish anything, then solves the brain teaser that she couldn't initially solve before (which was simply numbers laterally inverted making the final product "1 2 3 4 5 6). At which point she exclaims "woo-hoo!!" (proving that while the "Simpson gene" won't effect her, she's still a Simpson nonetheless), before correcting herself.
Meanwhile, Jasper visits the Kwik-E-Mart and empties all the ice cream in a walk-in cooler so he can freeze himself in that cooler and survive to see the future. Apu sees a money-making opportunity and advertising the frozen Jasper as "Frostilicus" renames the Kwik-E-Mart the Freak-E-Mart, which becomes a tourist trap. The Freak-E-Mart lasts briefly until the freezer fails, and Jasper thaws and emerges alive and well. Fearing he will lose his customers, Apu makes the Kwik-E-Mart into the Nude-E-Mart, a combination of a convenience store and a strip club.