Gene Structure and Function PDF

Gene Structure and Function Current estimates of the human genome ~20,000 protein-coding genes … seems insufficient. Two features of gene structure and function that suffices for executing the large array of functions needed by cells: Many genes are capable of generating multiple different pro...

Gene Structure and Function Current estimates of the human genome ~20,000 protein-coding genes … seems insufficient. Two features of gene structure and function that suffices for executing the large array of functions needed by cells: Many genes are capable of generating multiple different products. Individual proteins do not function by themselves. They form elaborate networks, thus, different combinations results in greater diversity of cellular functions. 11:14 AM 1 11:14 AM 2  Some chromosome regions, or even whole chromosomes, are high in gene content (“gene rich”), whereas others are low (“gene poor”). Abnormalities of gene-rich chromosomes or chromosomal regions tend to be much more severe clinically than similar-sized defects involving gene-poor Figure 2-7 Size and gene content of the 24parts human chromosomes. of the genome. Dotted diagonal line corresponds to the average density of genes in the genome, approximately 6.7 protein-coding genes per megabase (Mb). Chromosomes that are relatively gene rich are above the diagonal and trend 11:14to AMthe upper left. Chromosomes that are relatively gene poor are 3 11:14 AM 4  The Central Dogma of Molecular Biology DNA>RNA>Protein 11:14 AM 5 General structure of a typical human gene 11:14 AM 6  3 exons > disorders of hemoglobin 24 exons > inherited breast or breast and ovarian cancer 40 exons > inherited hypertrophic cardiomyopathy 11:14 AM 7 Pseudogenes DNA sequences that closely resemble known genes but are nonfunctional  Nonprocessed pseudogenes: were once functional but are now vestigial, inactivated by mutations in critical coding or regulatory sequences  Processed pseudogenes: formed by retrotransposition:  transcription  generation of DNA copy of mRNA (cDNA) by reverse transcription (reverse transcriptase enzyme)  integration into the genome at a different 11:14 AMlocation 8 11:14 AM 9 11:14 AM Code is degenerate 10 11:14 AM 11 11:14 AM 12 Not all genes in the genome can be actively expressed in every cell at all times Specific characteristics of chromatin are associated with active or repressed genes Epigenetics focus on reversible changes of chromatin landscape as determinants of gene function rather than on changes to the genome sequence itself 11:14 AM 13  Epigenetic changes can be transient or long lasting 11:14 AM 14 Extensive demethylation occurs during germ cell development and early stages of embryonic development to re-set chromatin environment Reprogramming steps involve conversion of 5-mC to 5-hmC as an intermediate in the demethylation of DNA 11:14 AM 15 Histone modifications include methylation, acetylation, and phosphorylation at the N-terminal tails of histones that extend out of the core nucleosome. Histone variants are products of different genes and their amino acid sequences are distinct from those of canonical histones. CENP-A is a variant histone related to histone H3, found in cetromeres Chromatin architecture, the genome adopts a highly ordered and dynamic 11:14 AM 16 11:14 AM 17 Topologically associating domains (TADs)  Chromosomes are organized in the 3D space of the nucleus to fulfill gene regulation  Chromosomes are spatially segregating in A- and B-type genomic compartments that represent active (euchromatin=open chromatin) and inactive (heterochromatin=repressive chromatin) domains, respectively 11:14 AM 18 Genomic compartmentalization can comprise multiple subcompartments  Nucleolus forms at site of hundreds of ribosomal genes of acrocentric chromosomes for preassembly of ribosomal subunits  Splicing speckles are nuclear domains enriched for splicing machinery  Promyelocytic leukemia (PML) bodies are involved in cell cycle processes and DNA repair 11:14 AM 19 Genomic compartments are subdivided into clusters of genomic interactions, termed topologically associating domains 11:14 AM 20 Reorganization of TAD architecture by chromosomal rearrangements can alter gene expression and may cause clinically apparent disease phenotypes  Genomic deletions can lead to TADs fusing  Duplications may form neo-TADs  Inversions reshuffle TADs  Translocations could alter interchromosomal contacts between nonhomologous 11:14 AM chromosomes 21 Sequence of DNA of a group of individuals is similar but not identical to the reference Allelic imbalance in gene expression Most genes show equivalent levels of biallelic expression, however, 5-20% of autosomal genes show unequal allelic 11:14 AM 23 expression 11:14 AM 24  ♀ Genomic imprinting and conversion of maternal and paternal imprints during passage through male or female gametogen esis 11:14 AM ♂ 25 XIST: inactive X specific transcrip ts [ncRNA] 11:14 AM 26