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Fig. 2 | Genome Medicine

Fig. 2

From: Genome annotation for clinical genomic diagnostics: strengths and weaknesses

Fig. 2

The generic gene model (not to scale). a The exons comprise the untranslated regions (UTRs), which are shown in red (the 5′ UTR depicted on the left and the 3′ UTR depicted on the right) and the coding sequence (CDS), which is shown in green. Many important regulatory regions lie outside of the exons of a gene. Intronic regulatory regions are shown in grey. Promoters are illustrated as yellow intergenic regulatory regions, although some genes have internal transcription start sites. The transcription start site (TSS) is positioned at the 5′ end of the UTR, where transcription starts. The 5′ UTRs of genes contain regulatory regions. The CDS start codon is the first codon of a messenger RNA (mRNA) from which a ribosome translates. The genomic sequence around the start codon often has the consensus sequence gccAcc|AUG|G (note that the important bases are highlighted here in bold, whereas the most crucial positions are –3 and +4 from the A of the AUG) [197], although, in very rare cases, a non-AUG start codon is used [198]. The stop codon, of which there are three in eukaryotes—UGA, UAG, UAA—is a nucleotide triplet sequence in an mRNA that gives the signal to terminate translation by binding release factors, causing the ribosome to release the peptide chain [199]. The 3′ untranslated region of genes contains regulatory regions. In particular, the 3′ UTR has binding sites for regulatory proteins such as RNA-binding proteins (RBP) and microRNAs (miRNA). Promoters are DNA sequences, between 100 and 1000 bp in length, where proteins that help control gene transcription bind to DNA [200]. These proteins can contain one or more DNA-binding domains that attach to a specific DNA sequence located next to the relevant gene [201]. Promoters regulate transcriptional machinery by moving it to the right place in the genome, as well as locating the 5′ end of the gene or an internal transcription start site. Approximately 40% of human genes have promoters situated in regions of elevated cytosine and guanine content, termed CpG islands [202]. A subset of promoters incorporate the variable TATA box sequence motif, which is found between 25 and 30 bp upstream of the TSS and is the position at the 5′ end of the UTR where transcription starts [203]. bd Pre-mRNA transcribed from DNA contains both introns and exons. An RNA and protein complex called the spliceosome undertakes the splicing out of introns, leaving the constitutive exons. Intronic and exonic splice enhancers and silencers help direct this procedure, such as the branch point (‘A’) and a poly-pyrimidine (poly-py) tract. The vast majority of introns have a GT sequence at the 5′ end that the branch point binds to. The intron is then cleaved from the 5′ exon (donor site) and then from the 3′ exon (acceptor site) [204] and a phosphodiester bond joins the exons, whereas the intron is discarded and degraded. During the formation of mature mRNA, the pre-mRNA is cleaved and polyadenylated. Polyadenylation occurs between 10 and 30 bp downstream from a hexamer recognition sequence that is generally AAUAAA, or AUUAAA, although other hexamer signal sequences are known [35] (as depicted in a). A specially modified nucleotide at the 5′ end of the mRNA, called the 5′ cap, helps with mRNA stability while it undergoes translation. This capping process occurs in the nucleus and is a vital procedure that creates the mature mRNA. e The translation of mRNA into protein by ribosomes occurs in the cytosol. Transfer RNAs (tRNAs), which carry specific amino acids, are read by the ribosome and then bound in a complementary manner to the mRNA. The amino acids are joined together into a polypeptide chain to generate the complete protein sequence for the coding sequence of the transcript. (Light blue background shading shows processes that occur in the nucleus. Light yellow background shading shows processes that occur in the cytosol, such as the translation of mRNAs into protein by ribosomes)

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