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August 03, 2010

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Same gene, different results

Nov. 2, 2008
Courtesy MIT
and World Science staff

Sci­en­tists are learn­ing to their sur­prise that a sin­gle gene very of­ten func­tions dif­fer­ently in dif­fer­ent parts of the body.

Genes gen­er­ally work by pro­duc­ing some mol­e­cule that serves a giv­en func­tion in the body. How­ev­er, sci­en­tists have long known one gene can pro­duce slightly dif­fer­ent forms of the same mol­e­cule, by skip­ping or in­clud­ing cer­tain al­ter­na­tive bits of ge­net­ic code.

The new re­search in­di­cates this phe­nom­e­non, known as al­ter­na­tive splic­ing, is far more prev­a­lent and varies more be­tween tis­sues than pre­vi­ously be­lieved. Nearly all hu­man genes, about 94 per­cent, gen­er­ate more than one form of their prod­ucts, re­search­ers re­ports in the Nov. 2 on­line edi­tion of the re­search jour­nal Na­ture. 

“A dec­ade ago, al­ter­na­tive splic­ing of a gene was con­sid­ered un­usu­al, ex­otic… it turns out that’s not true at al­l,” said Chris­to­pher Burge, sen­ior au­thor of the pa­per and a bi­olo­g­ist at the Mas­sa­chu­setts In­sti­tute of Tech­nol­o­gy.

Burge and col­leagues al­so found that in most cases the spe­cif­ic gene prod­uct de­pends on the tis­sue where the gene is ex­pressed, or ac­ti­vat­ed. The work paves the way for fu­ture stud­ies in­to the role of al­ter­na­tive pro­teins in spe­cif­ic tis­sues, in­clud­ing can­cer cells, he added.

Hu­man genes typ­ic­ally con­tain sev­er­al “ex­ons,” or DNA se­quences that code for ami­no acids, the build­ing blocks of large mol­e­cules called pro­teins. A sin­gle gene can pro­duce mul­ti­ple se­quences of ami­no acids, de­pend­ing on which ex­ons are in­clud­ed in the in­struc­tions that trav­el from the gene to a cel­l’s pro­tein-build­ing ma­chin­ery.

Two dif­fer­ent forms of the same pro­tein, known as iso­forms, can have dif­fer­ent, even op­po­site func­tions. For ex­am­ple, one pro­tein may set in mo­tion chains of ev­ents that lead cells to com­mit su­i­cide when nec­es­sary. A close rel­a­tive of the same pro­tein may in­stead pro­mote long­er cell sur­viv­al.

The re­search­ers found that the type of iso­form pro­duced of­ten de­pends strongly on the tis­sue. Cer­tain pro­tein iso­forms that are com­mon in the heart, for ex­am­ple, might be rare in the brain, so that the al­ter­na­tive ex­on func­tions like a mo­lec­u­lar switch. Sci­en­tists who study splic­ing have a gen­er­al idea of how tis­sue-spe­cif­icity may be achieved, but much less un­der­stand­ing of why iso­forms dis­play such tis­sue spe­cif­icity, Burge said.

One no­ta­ble find­ing was that peo­ple’s brains of­ten dif­fer in their ex­pres­sion of al­ter­na­tively spliced iso­forms, Burge and col­leagues said. Iso­form switch­ing al­so oc­curs in can­cer cells, they added: one such switch in­volves a met­a­bol­ic en­zyme and con­tri­butes to can­cer cells burn­ing large amounts of sug­ar and grow­ing more rap­id­ly. Learn­ing more about such switches could lead to po­ten­tial can­cer ther­a­pies, Burge said.

* * *

Scientists are learning to their surprise that a single gene very often functions differently in different parts of the body. Genes generally work by producing some molecule that serves a given function in the body. However, scientists have long known one gene can produce slightly different forms of the same molecule, by skipping or including certain alternative bits of genetic code. The new research indicates this phenomenon, known as alternative splicing, is far more prevalent and varies more between tissues than previously believed. Nearly all human genes, about 94 percent, generate more than one form of their products, researchers reports in the Nov. 2 online edition of the research journal Nature. “A decade ago, alternative splicing of a gene was considered unusual, exotic… it turns out that’s not true at all,” said Christopher Burge, senior author of the paper and a biologist at the Massachusetts Institute of Technology. Burge and colleagues also found that in most cases the specific gene product depends on the tissue where the gene is expressed, or activated. The work paves the way for future studies into the role of alternative proteins in specific tissues, including cancer cells, he added. Human genes typically contain several “exons,” or DNA sequences that code for amino acids, the building blocks of large molecules called proteins. A single gene can produce multiple sequences of amino acids, depending on which exons are included in the instructions that travel from the gene to a cell’s protein-building machinery. Two different forms of the same protein, known as isoforms, can have different, even opposite functions. For example, one protein may activate pathways that induce cells to commit suicide when necessary. A close relative of the same protein may instead promote longer cell survival. The researchers found that the type of isoform produced often depends strongly on the tissue. Certain protein isoforms that are common in the heart, for example, might be rare in the brain, so that the alternative exon functions like a molecular switch. Scientists who study splicing have a general idea of how tissue-specificity may be achieved, but much less understanding of why isoforms display such tissue specificity, Burge said. One notable finding was that people’s brains often differ in their expression of alternative spliced mRNA isoforms, Burge and colleagues said. Isoform switching also occurs in cancer cells. One such switch involves a metabolic enzyme and contributes to cancer cells burning large amounts of sugar and growing more rapidly. Learning more about such switches could lead to potential cancer therapies, Burge said.