Media Releases

U of T researchers crack “splicing code,” solve a mystery underlying biological complexity

May 5, 2010

TORONTO, ON – Researchers at the Uni­ver­si­ty of Toron­to have dis­cov­ered a fun­da­men­tal­ly new view of how liv­ing cells use a lim­it­ed num­ber of genes to gen­er­ate enor­mous­ly com­plex organs such as the brain.

In a paper pub­lished on May 6 in the jour­nal Nature enti­tled “Deci­pher­ing the Splic­ing Code,” a research team led by Pro­fes­sors Bren­dan Frey and Ben­jamin Blencowe of the Uni­ver­si­ty of Toron­to describes how a hid­den code with­in DNA explains one of the cen­tral mys­ter­ies of genet­ic research – name­ly how a lim­it­ed num­ber of human genes can pro­duce a vast­ly greater num­ber of genet­ic mes­sages. The dis­cov­ery bridges a decade-old gap between our under­stand­ing of the genome and the activ­i­ty of com­plex process­es with­in cells, and could one day help pre­dict or pre­vent dis­eases such as can­cers and neu­rode­gen­er­a­tive dis­or­ders.

When the human genome was ful­ly sequenced in 2004, approx­i­mate­ly 20,000 genes were found. How­ev­er, it was dis­cov­ered that liv­ing cells use those genes to gen­er­ate a much rich­er and more dynam­ic source of instruc­tions, con­sist­ing of hun­dreds of thou­sands of genet­ic mes­sages that direct most cel­lu­lar activ­i­ties. Frey, who has appoint­ments in Engi­neer­ing and Med­i­cine, likens this dis­cov­ery to “hear­ing a full orches­tra play­ing behind a locked door, and then when you pry the door open, you dis­cov­er only three or four musi­cians gen­er­at­ing all that music.”

To fig­ure out how liv­ing cells gen­er­ate vast diver­si­ty in their genet­ic infor­ma­tion, Frey and post­doc­tor­al fel­low Yoseph Barash devel­oped a new com­put­er-assist­ed bio­log­i­cal analy­sis method that finds ‘code­words’ hid­den with­in the genome that con­sti­tute what is referred to as a ‘splic­ing code’. This code con­tains the bio­log­i­cal rules that are used to gov­ern how sep­a­rate parts of a genet­ic mes­sage copied from a gene can be spliced togeth­er in dif­fer­ent ways to pro­duce dif­fer­ent genet­ic mes­sages (mes­sen­ger RNAs). “For exam­ple, three neurex­in genes can gen­er­ate over 3,000 genet­ic mes­sages that help con­trol the wiring of the brain,” says Frey.

“Pre­vi­ous­ly, researchers couldn’t pre­dict how the genet­ic mes­sages would be rearranged, or spliced, with­in a liv­ing cell,” Frey said. “The splic­ing code that we dis­cov­ered has been suc­cess­ful­ly used to pre­dict how thou­sands of genet­ic mes­sages are rearranged dif­fer­ent­ly in many dif­fer­ent tis­sues.” Blencowe’s group, includ­ing grad­u­ate stu­dent John Calar­co, gen­er­at­ed exper­i­men­tal data used to derive and test pre­dic­tions from the code.  “That the splic­ing code can make accu­rate pre­dic­tions on such a large scale is a major step for­ward for the field,” says Blencowe.

Frey and Blencowe attribute the suc­cess of their project to the close col­lab­o­ra­tion between their team of tal­ent­ed com­pu­ta­tion­al and exper­i­men­tal biol­o­gists. “Under­stand­ing a com­plex bio­log­i­cal sys­tem is like under­stand­ing a com­plex elec­tron­ic cir­cuit. Our team ‘reverse-engi­neered’ the splic­ing code using large-scale exper­i­men­tal data gen­er­at­ed by the group,” Frey said.

Prof. Frey has appoint­ments to the Cana­di­an Insti­tute for Advanced Research and the U of T’s Depart­ment of Elec­tri­cal and Com­put­er Engi­neer­ing, the Bant­i­ng & Best Depart­ment of Med­ical Research (BBDMR) and the Depart­ment of Com­put­er Sci­ence. Prof. Blencowe works in the University’s Don­nel­ly Cen­tre for Cel­lu­lar & Bio­mol­e­c­u­lar Research and has appoint­ments in the BBDMR and Depart­ment of Mol­e­c­u­lar Genet­ics

The research was sup­port­ed by Genome Cana­da, the Ontario Genomics Insti­tute, the Cana­di­an Insti­tutes for Health Research, Nation­al Can­cer Insti­tute of Cana­da, and Microsoft Research. The authors of the study are: Yoseph Barash, John A. Calar­co, Wei­jun Gao, Qun Pan, Xinchen Wang Ofer Shai, Ben­jamin J. Blencowe & Bren­dan J. Frey.

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Mario Pidut­ti
Fac­ul­ty of Applied Sci­ence and Engi­neer­ing
Uni­ver­si­ty of Toron­to