DI­GEST

How did our brains get so big? Re­searchers are be­gin­ning to find out. EL­IZ­A­BETH FINKEL re­ports.

Cosmos - - Contents -

About six mil­lion years ago our hu­man an­ces­tors branched off the pri­mate fam­ily tree, leav­ing their cousins – the an­ces­tors of chim­panzees – in the African dust.

They made sim­ple tools and, thus equipped, even­tu­ally trav­elled out of Africa.

The evo­lu­tion­ary leap that started the jour­ney was the mush­room­ing of the hu­man brain. A mod­ern hu­man brain is three times larger than a chimp’s; the most en­larged re­gion is the six-lay­ered neo­cor­tex, a part of the cere­bral cor­tex that is the seat of rea­son­ing and lan­guage.

How did this cir­cuit up­grade take place? For the past decade, sci­en­tists have been com­par­ing the DNA of chim­panzees and hu­mans to look for clues. The most re­cent dis­cov­ery comes from Wieland Hut­tner’s lab at the Max Planck In­sti­tute in Ger­many. Re­mark­ably, they showed that just a sin­gle let­ter change in the DNA of one gene trig­gered an in­crease in a pop­u­la­tion of stem cells called basal ra­dial glia. Th­ese cells are thought to have pow­ered the ex­pan­sion of the hu­man cere­bral cor­tex. The find­ing was pub­lished in Science Ad­vances last De­cem­ber.

The dra­matic find­ing is the lat­est in a se­ries of rev­e­la­tions about the DNA up­grades that de­liv­ered the hu­man brain. Hu­man and chim­panzee genomes are 98.8% the same.

In­trigu­ingly, within many of the re­gions that dif­fer, it looks as if chunks of DNA in the hu­man had been Xeroxed – mean­ing hu­mans ac­quired “back-up copies” of par­tic­u­lar genes, That made them ripe for some evo­lu­tion­ary tin­ker­ing; if the copy hap­pens to ac­quire a few cod­ing er­rors, there’s no drama – there’s still the func­tion­ing orig­i­nal. Once in a while how­ever, a copy­ing er­ror might lead to a new func­tion that is use­ful.

Six mil­lion years ago, around the time our an­ces­tors were branch­ing off from non-hu­man pri­mates, there was a burst of th­ese gene du­pli­ca­tions. Smok­ing guns! Prob­lem is, there were thou­sands of them.

To get a clue as to which ones might be in­volved in the hu­man brain up­grade, re­searchers tested to see whether re­lated genes in mice were in­volved in the de­vel­op­ment of their brain.

One suc­cess came in 2012, when Cé­cile Char­rier at the Scripps Re­search In­sti­tute in Cal­i­for­nia and her col­leagues took a closer look at a du­pli­cated hu­man gene named SRGAP2C. It was a slightly al­tered copy of the orig­i­nal found in chimps and mice, and it was ac­tive in their de­vel­op­ing brains. The sci­en­tists came up with an ir­re­sistible ex­per­i­ment: they ge­net­i­cally en­gi­neered the hu­man copy into em­bry­onic mice.

As neu­rons de­velop, they ac­quire spines that act like an­ten­nae for re­ceiv­ing mes­sages from other neu­rons. But the spines stop sprout­ing once the neu­rons ma­ture. Char­rier and her team found that in­tro­duc­ing the hu­man backup gene, SRGAP2C, de­layed the mat­u­ra­tion so spines kept sprout­ing, which en­abled them to make more con­nec­tions. The ex­per­i­ment showed how, through the copy­ing and then tweak­ing of a sin­gle gene, evo­lu­tion in­creased the cir­cuit com­plex­ity of the hu­man brain.

HU­MANS AC­QUIRED “BACK- UP COPIES” OF PAR­TIC­U­LAR GENES, THAT MADE THEM RIPE FOR SOME EVO­LU­TION­ARY TIN­KER­ING.

The lat­est work fol­lows a sim­i­lar plot line. Marta Flo­rio, a PHD stu­dent in the Hut­tner lab stud­ied an­other backup copy of a gene that is present in hu­mans but ab­sent from chimps and mice. It is called ARHGAP11B. When the hu­man ver­sion was in­tro­duced into de­vel­op­ing mice, it caused a par­tic­u­lar pop­u­la­tion of brain stem cells – basal ra­dial glia – to in­crease their rounds of mul­ti­pli­ca­tion. Not only did mice dou­ble the num­ber of th­ese stem cells in some cases their bal­loon­ing brains started fold­ing to fit into the skull – just as the brains of pri­mates do.

That find­ing was re­ported in Science in 2015. The lat­est find­ing is that just a sin­gle let­ter change in the ARHGAP11B DNA is able to in­crease the mul­ti­pli­ca­tion of basal ra­dial glia.

So are th­ese mice any smarter? The Ger­man team has yet to test them. But at least one strain of mice are smarter to­day for hav­ing ac­quired a hu­man gene.

The FOXP2 gene is needed to turn thoughts into speech; hu­man fam­i­lies who lack the func­tional gene show de­fects in lan­guage and vo­cal­i­sa­tion. Ac­cord­ing to a paper pub­lished in 2014 by Chris­tiane Schrei­weis at the Max Planck In­sti­tute and col­leagues at MIT, when the hu­man form of this gene was in­tro­duced into mice, they got bet­ter at learn­ing mazes and squeaked more of­ten.

As stun­ning as th­ese re­sults are, re­searchers are still far from pro­vid­ing a man­i­fest of the up­grades that de­liv­ered the hu­man brain. “Evo­lu­tion went through a process of trial and er­ror over mil­lions of years,” says neu­ro­sci­en­tist Seong Sen Tan of the Florey In­sti­tute in Mel­bourne. “There will be nu­mer­ous switches.”

CREDIT: MARTA FLO­RIO / WIELAND B. HUT­TNER / MAX PLANCK IN­STI­TUTE OF MOLEC­U­LAR CELL BI­OL­OGY AND GE­NET­ICS

The fold­ing on the right side of this mouse em­bryo’s cor­tex re­flects the in­creased growth stim­u­lated by the in­ser­tion of a hu­man gene into that side of the brain.

An in­crease in the num­ber of stem cells known as basal ra­dial glia is thought to have pow­ered the ex­pan­sion of the hu­man neo­cor­tex. UP­GRAD­ING THE HU­MAN BRAIN Sub­ven­tric­u­lar zone Mouse neo­cor­tex Hu­man neo­cor­tex KEY api­cal ra­dial glia basal in­ter­me­di­ate pro­gen­i­tor basal ra­dial glia mi­grat­ing neu­rons

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