They also cause headaches for researchers who are trying to understand our genome. Scientists sequence genomes by breaking long stretches of DNA into more manageable fragments. They then decipher each piece separately, before assembling the pieces into a whole. But when genes are duplicated, fragments of the copies are almost indistinguishable from fragments of the originals, which causes confusion. It’s like trying to assemble several jigsaw puzzles that are only slightly different: When their pieces are jumbled up, it looks like they all come from a single puzzle.
That was the case for NOTCH2NL. In earlier drafts of the human genome, it looked like one gene. But when the latest (and 20th) draft was released in December 2013, Jacobs and his colleagues realized that this mysterious gene was actually three genes. They’re known as NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC. They’re 99.7 percent identical to each other. And they have a convoluted history.
In the common ancestor of all great apes, there was just one gene: NOTCH2. At some point, it was duplicated, but only partially. Its doppelganger, the first NOTCH2NL gene, was missing important sections, and so didn’t work properly. It was useless, an instruction manual with random chapters torn out. To this date, chimps and gorillas still have these dead versions of NOTCH2NL.
But between 3 and 4 million years ago, in the ancestors of humans, something special happened. The original NOTCH2 gene partly overwrote its broken duplicate. This process, known as gene conversion, revived NOTCH2NL, allowing it to play an active role in its owners’ biology. And having been resurrected, it duplicated twice more, creating the A, B, and C genes that we have today.
While Jacobs’s team was learning all of this, Ikuo Suzuki and colleagues from KU Leuven, a university in Belgium, were homing in on the NOTCH2NL genes through a different route. They started by identifying genes that have three characteristics: They arose from duplication events, are strongly active in the developing brain, and are unique to humans. Suzuki and his team came up with a shortlist of 35 genes, and introduced several of these into the brains of embryonic mice to see what would happen.
One gene—NOTCH2NLB—had a particularly interesting effect on the radial glia, the cells responsible for building a brain. The radial glia are like factories that manufacture two products: neurons and more factories. Both Suzuki and Jacobs found that NOTCH2NL genes nudge the glia toward the latter: They make more of themselves. As their numbers swell, they collectively churn out more neurons and build bigger brains. By influencing the radial glia, the NOTCH2NL genes might have contributed to the evolution of our large brains and vaunted intellects.
These changes could have come at a cost. The NOTCH2NL genes are so similar that even our cells can get them confused. As a result, the stretch of DNA where these genes reside is very unstable. Sometimes, it gets duplicated. Sometimes, it’s deleted. Sometimes, the A gene might overwrite the B one, or vice versa. These genetic upheavals can lead to developmental disorders.