UN­DER­STAND­ING AUTISM

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gene called neu­roli­gin-3 passes on the con­di­tion. In other cases, ASD has been linked to ab­nor­mal or ex­tra chunks of DNA on chro­mo­some 15.

The vast ma­jor­ity of autism cases don’t have this clear link. Some sus­pect it might arise from de­fects in mul­ti­ple genes act­ing to­gether. Over the past two decades re­searchers have be­come mas­ter­ful at fish­ing them out. One fruit­ful ap­proach has been to read the DNA se­quence of un­af­fected par­ents and their autis­tic child, to see where the child’s DNA dif­fers. This has re­vealed that of­ten the child has ac­quired new DNA mu­ta­tions; in about 10% of cases siz­able chunks of their DNA has been ei­ther du­pli­cated or deleted – so-called ‘copy num­ber vari­a­tions’.

While hun­dreds of genes have been linked to ASD, they haven’t shed much light on the na­ture of the dis­or­der. The genes tend to par­tic­i­pate in global pro­cesses: for ex­am­ple, the CHD8 gene reg­u­lates how DNA is pack­aged, while the SCN2A gene codes for a sodium chan­nel that reg­u­lates elec­tri­cal trans­mis­sion be­tween brain neu­rons. IN HIS HAR­VARD LAB, faced with so many po­ten­tial sus­pects, An­der­son de­cided to fol­low a hunch about chro­mo­some 15. He was com­pelled by ev­i­dence of the yin-yang be­havioursef­fect that fol­lowed from hav­ing gain­ing too few or too many bits of this chro­mo­some.

As­so­ciated with about 2% of ASD cases, it is one of the few ge­netic causes of autism that can be de­tected un­der the mi­cro­scope. A band on chro­mo­some 15 is slightly big­ger than it ought to be. That’s be­cause this re­gion, known as 15q11-13, has been trip­li­cated. (Cu­ri­ously, it is only as­so­ciated with ASD when in­her­ited from the mother.)

On the other hand, chil­dren who have lost this same bit of chro­mo­some are the op­po­site of autis­tic; they have An­gel­man’s Syn­drome, ev­i­denced by a lower IQ and hy­per-so­cial be­hav­iour. They smile and laugh, and make strong eye con­tact.

One of the genes that stood out in the 15q re­gion was ubiq­ui­tin E3-lig­ase (Ube3a). Other trawls through the DNA of peo­ple af­fected by ASD were also un­earthing copy num­ber in­creases in the same gene. But its known func­tions – tag­ging some pro­teins for de­struc­tion, and turn­ing genes on and off – pro­vided few hints as to why it might cause autism.

So the An­der­son team cre­ated mice with mul­ti­ple copies of the Ube3a gene. Sure enough, the an­i­mals showed symp­toms that placed them on the mouse autism spec­trum. Males were less in­ter­ested in new fe­males, vo­calised less, and groomed ob­ses­sively. The more copies of the gene, the more se­vere these be­hav­iours be­came.

Delet­ing Ube3a had the op­po­site ef­fect. Mice be­came more so­cial, spend­ing an av­er­age of 15 min­utes so­cial­is­ing with new­com­ers in­stead of the usual five.

How was Ube3a do­ing this? The re­searchers took a look at which genes were af­fected by the pres­ence of the ex­tra copies. Genes pro­vide recipes for pro­teins. It seemed Ube3a was act­ing like the mas­ter chef and mod­i­fy­ing the menu. The pro­duc­tion of about 200 dishes was be­ing di­alled down, while 400 oth­ers were ramped up.

Daunt­ingly com­plex? Not for this team of data de­tec­tives. An­der­son and his col­leagues checked the ASD gene data­bases to see which pro­teins on the mod­i­fied menu also be­longed to autism net­works. They then checked to see which of the autism- and Ube3a-re­lated pro­teins bound to each other. Like step­ping stones, the idea was to con­nect the pro­teins in a path­way that might lead to autism.

One of the pro­teins di­alled down is called cere­bellin 1. The more copies of the Ube3a gene, the lower its pro­duc­tion. The pro­tein-bind­ing net­work showed cere­bellin 1 snapped to­gether with two in­ter­est­ing autism-re­lated genes: neurexin 1 and glu­ta­mate re­cep­tor delta sub­unit 1 (GRID 1). All three act at the synapse, the space be­tween neu­rons where mes­sages are re­layed by neu­ro­trans­mit­ters.

The trio form a sand­wich across the synapse, with neurexin 1 at the send­ing side, and GRID 1 at the re­ceiv­ing side and cere­bellin 1 in the mid­dle. These pro­teins help sol­der par­tic­u­lar neu­rons to­gether to form a cir­cuit.

Now the ques­tion be­came: what types of neu­rons use this triple sol­der? There are dozens of types, iden­ti­fied by the trans­mit­ters they use. To find out, the team used ge­netic en­gi­neer­ing to insert ex­tra copies of the mas­ter chef gene into spe­cific neu­rons. It was only when ex­cess Ube3a was in­tro­duced into glu­ta­mater­gic or dopamin­er­gic neu­rons – both as­so­ciated with re­ward-de­pen­dent be­hav­iours – that mice ex­pe­ri­enced so­cial prob­lems.

Genes pro­vide recipes for pro­teins. It seemed the Ube3a gene was act­ing like the mas­ter chef and mod­i­fy­ing the menu.

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