July/August 2007

Guide Dogs

Continued from page 4

By Katherine Bourzac, SM '04

What Makes Us Mammals
Comparing the dog genome with the mouse and human genomes helped researchers identify a host of regulatory elements; further analysis showed that in all three mammals, half of those elements are clustered around only about 240 genes. In other words, a whopping 50 percent of our most conserved elements appear to regulate not much more than 1 percent of our genes.

So what do those genes do to deserve such special treatment? It turns out that they play pivotal roles during development. They control our body plan, the biological equivalent of a blueprint. By dictating the configuration of our spines, the structure of our brains, and the position of our opposable thumbs, they make us vertebrates, mammals, primates.

"It's of course critically important that you produce a foot where your foot goes and not on your head sometimes by accident," says Lindblad-Toh. "What we think we've found is that around these 200 or so genes sit a large proportion of these regulatory elements. They are basically the master regulators of the master genes that make mammals mammals." Some of these clustered regulatory elements are so important that they are better conserved between species than genes are.

An analysis of the opossum genome published by the Broad this past May further supports Lindblad-Toh's ­hypothesis that there are mammalian master regulators. Opossums are on a different branch of the mammalian family tree: they are marsupials, while humans, dogs, and mice are eutherians--mammals with placentas. "For every genome that we add on, we keep building on the hypothe­sis that the functional 5 percent from human, mouse, and dog genomes is mammalian- and eutherian-specific," says Lindblad-Toh. "Looking at the opossum and other major branches on the vertebrate tree, we see that there's innovation that's added on." That is, opossums don't share the entirety of the 5 percent that placental mammals do. Much of the variation in the regulatory elements in marsupials is around the body-plan genes. These variations may be what make opossums marsupials, and what does not vary may be an important part of what constitutes mammalness.

Lindblad-Toh says it's too early to ask what makes a primate a primate, or what makes humans human. It seems likely, though, that development in neural pathways is regu­lated by primate-specific genes. Each order, each species of animal probably has its own innovations, controlled by master regulators in non-gene areas of the genome.

Right now, Lindblad-Toh says, she and other Broad researchers are just trying to assemble a basic catalogue of these master regulators. Once more species have been sequenced, it will be possible to start answering the bigger questions. As that menagerie of genomes continues to grow, dogs--long man's best friends in the field and on the farm--are proving to be valuable companions in the lab as well.