The primary RNA transcript of the β-globin gene contains two introns, ~100 and 850 bp in length, that need to be removed and the remaining RNA segments joined together to form the mature mRNA. The process of RNA splicing, described generally earlier, is typically an exact and highly efficient one; 95% of β-globin transcripts are thought to be accurately spliced to yield functional globin mRNA. The splicing reactions are guided by specific sequences in the primary RNA transcript at both 5′ and 3′ ends of introns. The 5′ sequence consists of nine nucleotides, of which two (the dinucleotide GT [Gu in the RNA transcript] located in the intron immediately adjacent to the splice site) are virtually invariant among splice sites in different genes (see Fig. 1). The 3′ sequence consists of approximately a dozen nucleotides, of which, again, two—the AG located immediately 5′ to the intron-exon boundary—are obligatory for nor mal splicing. The splice sites themselves are unrelated to the reading frame of the particular mRNA. In some instances, as in the case of intron 1 of the β-globin gene, the intron actually splits a specific codon (see Fig. 1).

Fig2. Nucleotide sequence of the complete human β-globin gene. The sequence of the 5′ to 3′ strand of the gene is shown. Tan areas with capital letters represent exonic sequences corresponding to mature mRNA. Lowercase letters indicate introns and flanking sequences. The CAT and TATA box sequences in the 5′ flanking region are indicated in brown. The GT and AG dinucleotides important for RNA splicing at the intron-exon junctions and the AATAAA signal important for addition of a polyA tail are also highlighted. The ATG initiator codon (AuG in mRNA) and the TAA stop codon (uAA in mRNA) are shown in red letters. The amino acid sequence of β-globin is shown above the coding sequence. (Original data from Lawn RM, Efstratiadis A, O'Connell C, et al: The nucleotide sequence of the human β-globin gene. Cell 21:647–651, 1980.)

The medical significance of RNA splicing is illustrated by the fact that variants within the conserved sequences at the intron-exon boundaries commonly impair RNA splicing, with a concomitant reduction in the amount of normal, mature β-globin mRNA; alterations in the GT or AG dinucleotides mentioned earlier invariably eliminate normal splicing of the intron containing the variant.

Alternative Splicing

As just discussed, when introns are removed from the primary RNA transcript by RNA splicing, the remaining exons are spliced together to generate the final, mature mRNA. However, for most genes, the primary transcript can follow multiple alternative splicing pathways, leading to the synthesis of multiple related but different mRNAs, each of which can be subsequently translated to generate different protein products. Some of these alternative events are tissue or cell type specific, and, to the extent that such events are determined by primary sequence, they are subject to allelic variation between different individuals. Nearly all human genes undergo alternative splicing to some degree, and it has been estimated that there are an average of two or three alternative transcripts per gene in the human genome, thus greatly expanding the information content of the human genome beyond the ~20,000 protein-coding genes. The regulation of alternative splicing appears to play a particularly impressive role during brain development, where it may contribute to generating the high levels of functional diversity needed in the nervous system. The reason for this may be because genes expressed in the brain tend to be larger in size and have more exons than those expressed in other tissues. Consistent with this, susceptibility to a number of neurodevelopmental conditions has been associated with shifts or disruption of alternative splicing patterns and other spontaneous, rare germline, and even somatic events.

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مواضيع ذات صلة

Abnormalities of Chromosome Structure

Impact of Genomic Variation

Variation in individual Genomes

Variation in gene Expression and its relevance to medicine

Allelic Imbalance in gene expression

Gene expression as the integration of Genomic and Epigenomic signals

Epigenetic and Epigenomic aspects of Gene expression

DNA Microarray Technology

Initiation of Transcription

Fundamentals of Gene Expression

Cell cycle checkpoints

Deoxyribonucleic acid replication