38 THE SCIENTIST | the-scientist.com
S
eventeen years ago, the completion of the Human Genome
Project revealed that there are around 20,000 protein-coding
genes in the human genome—a puzzling result, given our
intricate biology. Thanks to the advancement of large-scale proteomic
studies over the decade following that milestone, researchers realized
that some human cells contain billions of different polypeptides.
Researchers realized that each gene can encode an array of proteins.
The process of alternative splicing, which had first been observed 26
years before the Human Genome Project was finished, allows a cell
to generate different RNAs, and ultimately different proteins, from
the same gene. Since its discovery, it has become clear that alterna-
tive splicing is common and that the phenomenon helps explain how
limited numbers of genes can encode organisms of staggering com-
plexity. While fewer than 40 percent of the genes in a fruit fly undergo
alternative splicing, more than 90 percent of genes are alternatively
spliced in humans.Astoundingly, some genes can be alternatively spliced to
generate up to 38,000 different transcript isoforms, and each of
the proteins they produce has a unique function. Like the chap-
ters of a book, coding segments of the genome, known as exons,
appear in series, and alternative splicing works by including or
leaving out some of these genomic passages. Some chapters are
required—that is, they are found in every transcript—and some
are optional, so-called alternative exons. The differential splic-
ing of these regions from an RNA transcript creates customized
and condensed genetic messages. Molecular editors control the
complicated flurry of exon selection by recognizing the chapters
needed for a given protein and discarding the others. The final
arrangement of exons in a spliced RNA molecule shapes the
resulting protein’s structure and function.
Although much remains to be learned about how these molecular
editors work, it is now clear that they can have serious consequencesIt’s now clear that cells can carve up transcripts in diff erent ways to generate a variety of proteins
from the same gene. Yet many questions remain about alternative splicing and its eff ects.BY GABRIELLE M. GENTILE, HANNAH J. WIEDNER, EMMA R. HINKLE, AND JIMENA GIUDICE