Figure 1.25 Continued sequence from AATAAA to AATAAG (Higgs et al. 1983). Accumulation of mRNA was reduced and the transcripts were noted to fail to terminate normally, continuing to 'read through' past the normal poly(A) addition site and revealing decoupling of the normal processes of termination of transcription and RNA 3' processing (Whitelaw and Proudfoot 1986).

1.3.9 Sequence diversity in noncoding DNA modulating gene expression

A diverse array of regulatory events control the process of transcription ranging from protein-DNA interactions involving the proximal promoter region upstream of the transcriptional start site to more distant regulatory regions. In the HBB gene promoter region 'CACCC' box elements have been shown to be important, i nteracting with specific transcription factors such as erythroid Kruppel-like factor (KLF). A proximal CACCC element has been shown to be the site of a number of single nucleotide variants that disrupt the consensus binding site for the interacting proteins leading to reduced gene expression and p+ thal-assaemia.

An early example was a C to G nucleotide substitution 87 nt upstream of the transcriptional start site (HBB:c.-137C>G) which changed the CACCC box to

Normal isoform I Alternative isoform

Consensus donor site

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