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New insights into the role of cis-ac...

Hefferon, Timothy W.

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New insights into the role of cis-acting sequences in the splicing of a constitutive exon.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	New insights into the role of cis-acting sequences in the splicing of a constitutive exon./
作者:	Hefferon, Timothy W.
面頁冊數:	104 p.
附註:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1659.
Contained By:	Dissertation Abstracts International65-04B.
標題:	Biology, Genetics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3130695
ISBN:	0496779435

New insights into the role of cis-acting sequences in the splicing of a constitutive exon.
Hefferon, Timothy W.

New insights into the role of cis-acting sequences in the splicing of a constitutive exon. - 104 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1659.

Thesis (Ph.D.)--The Johns Hopkins University, 2004.

RNA splicing is the fundamental biological process by which ribonucleoproteins in the cell nucleus identify, excise, and join short coding sequences called exons from much longer, intron-containing precursor RNAs. Although highly conserved signals aid in the accurate identification of exons, aberrant splicing often takes place despite their presence. We used a minigene and cross-species analysis to assess the contribution of less conserved splicing signals to the clinically relevant mis-splicing of a constitutive exon in the CFTR gene. Our results showed that suboptimal 5 ' splice sites up- and downstream of this exon, as determined by sequence composition at the +3 to +6 positions, predispose exon 9 to be skipped in almost all humans. Several groups have shown that a 5-thymidine variant (termed 5T) present in 10% of the population substantially increases mis-splicing, sometimes resulting in disease phenotypes. We demonstrated that clinical outcome correlated with the number of repeats in a TG tract adjacent to the 5T, and that the TG tract forms an RNA hairpin structure. The length and stability of the hairpin altered splicing efficiency of the 5T variant. Finally, we recognized that the TG tract and the adjacent T tract created a new type of repeat sequence. We hypothesized that nucleotides at the interface of TG and T tracts are a mutational hotspot, vulnerable to what we have termed interface transversion. Using custom software, we identified thousands of other examples of juxtaposed mono- and dinucleotide tracts in the human genome. Analysis of several of these, chosen randomly, revealed the same type of variation seen in the CFTR intron 8 TG-T sequence. These studies reveal that variation in cis sequence elements, in addition to those typically studied, can have profound consequences upon splicing and upon penetrance of disease phenotypes in a substantial portion of the population.

ISBN: 0496779435Subjects--Topical Terms:

1017730
Biology, Genetics.

New insights into the role of cis-acting sequences in the splicing of a constitutive exon.
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