When an uninvited guest turns up at your house, they don't knock down the walls, but they do move things around, and your usual routes through the rooms get confusing. In people with Down syndrome, that guest is an extra copy of chromosome 21, and for a long time scientists couldn't pin down what exactly it changes in the way the body works.
To find out, they created mice with the same extra chromosome, but removed all the unrelated genes that could muddy the picture. The mice were fed ordinary food, and before long their sugar and fat metabolism went off the rails: cells stopped responding properly to insulin, and the balance of fats in the blood shifted. In females these disruptions were stronger than in males.
Now the scientists can restore a normal dose to each triplicated gene, one at a time, and watch what changes. It's like tidying up a house: first you put one thing back where it belongs, then another, and gradually it becomes clear what set everything off in the first place.
On ordinary chow, female Ts66Yah mice weigh more than their euploid counterparts even though they eat and move just as much, while males have a lower body temperature during the resting phase. And on a high-fat diet, males actually improve their insulin sensitivity, which looks paradoxical against the backdrop of obesity.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.