TY - JOUR
T1 - Human-mouse comparative analysis reveals that branch-site plasticity contributes to splicing regulation
AU - Kol, Guy
AU - Lev-Maor, Galit
AU - Ast, Gil
N1 - Funding Information:
We thank Ido Carmel, Rotem Sorek, Amir Goren, Noa Sela and Alon Magen for sharing data sets. This work was supported by a grant from the Israel Science Foundation (1449/ 04 and 717/01) and, in part, by a grant from the German Israeli Project Cooperation Program, FD Hope, and the Chief Scientist of the Israel Health Ministry to G.A.
PY - 2005/6/1
Y1 - 2005/6/1
N2 - The formation of base-pairing between the branch-site (BS) sequence and the U2 snRNP is an important step in mRNA splicing. We developed a new algorithm to identify both the BS sequence and the polypyrimidine tract (PPT) and validated its predictions experimentally. To assess BS conservation between human and mouse, we assembled and analyzed 46 812 and 242 constitutively and alternatively spliced orthologs of human-mouse intron pairs, respectively. Combinations of BSs and PPTs can be found in most of the constitutive and alternative introns. The average distance between the BS and the 3′ splice site (3′ss) is 33-34 nt. Acceptor-like AG dinucleotides that resided between the predicted BS and the 3′ss were found to appear mostly within 5 nt, but not more than 19 nt, downstream of the BS. However, although 32% of homologous alternatively spliced BS sequences were fully conserved between human and mouse, only a small fraction (3%) of homologous constitutive counterparts was fully conserved. This indicates that the full sequence of the BS is under weak purifying selection in constitutively spliced introns and further strengthens the view that the BS sequence is just one of several factors determining the ability of the splicing machinery to identify the BS location. Mutations in the putative BS revealed a shift from constitutive to alternative splicing, and it also controls the inclusion/skipping ratio in alternative splicing. This suggests a role for BS sequences in regulated splicing.
AB - The formation of base-pairing between the branch-site (BS) sequence and the U2 snRNP is an important step in mRNA splicing. We developed a new algorithm to identify both the BS sequence and the polypyrimidine tract (PPT) and validated its predictions experimentally. To assess BS conservation between human and mouse, we assembled and analyzed 46 812 and 242 constitutively and alternatively spliced orthologs of human-mouse intron pairs, respectively. Combinations of BSs and PPTs can be found in most of the constitutive and alternative introns. The average distance between the BS and the 3′ splice site (3′ss) is 33-34 nt. Acceptor-like AG dinucleotides that resided between the predicted BS and the 3′ss were found to appear mostly within 5 nt, but not more than 19 nt, downstream of the BS. However, although 32% of homologous alternatively spliced BS sequences were fully conserved between human and mouse, only a small fraction (3%) of homologous constitutive counterparts was fully conserved. This indicates that the full sequence of the BS is under weak purifying selection in constitutively spliced introns and further strengthens the view that the BS sequence is just one of several factors determining the ability of the splicing machinery to identify the BS location. Mutations in the putative BS revealed a shift from constitutive to alternative splicing, and it also controls the inclusion/skipping ratio in alternative splicing. This suggests a role for BS sequences in regulated splicing.
UR - http://www.scopus.com/inward/record.url?scp=20444470310&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddi164
DO - 10.1093/hmg/ddi164
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AN - SCOPUS:20444470310
SN - 0964-6906
VL - 14
SP - 1559
EP - 1568
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 11
ER -