The Human Genome Ch3 Genetics PDF

The Human Genome Gene structure and function Chapter 3 Information content of the human genome Genetic information phenotype. Information content of the human genome Many genes are capable of generating multiple different products, not just one. Individual proteins do not function by themselves. The...

The Human Genome Gene structure and function Chapter 3 Information content of the human genome Genetic information phenotype. Information content of the human genome Many genes are capable of generating multiple different products, not just one. Individual proteins do not function by themselves. They form networks, often involving many different proteins and regulatory RNAs. The combinatorial nature of protein networks results in an even greater diversity of possible cellular functions. The Central Dogma: DNA RNA Protein The genomic DNA directs the synthesis and sequence of RNA, RNA directs the synthesis and sequence of polypeptides, and specific proteins are involved in the synthesis and metabolism of DNA and RNA. Gene Organization and Structure - Exons are the segments of genes that ultimately determine the amino acid sequence of the protein. - Most of the genes, the coding sequences (exons) are interrupted by one or more noncoding regions (introns). - The introns are initially transcribed into RNA in the nucleus but are not present in the mature mRNA in the cytoplasm because they are spliced out. Gene families Many genes belong to gene families, which share important characteristics: 1- Structural: similar DNA sequences and encode polypeptides with closely related amino acid sequences and function. 2- Functional: produce proteins that work together as a unit to participate in the same process. e.g. Globin family Pseudogenes Pseudogenes are nonfunctional DNA sequences resembling known genes, with approximately 20,000 pseudogenes scattered throughout the genome. Pseudogenes exist in two main types: A- Non-processed pseudogenes are "dead" genes resulting from gene duplication, with mutations rendering them nonfunctional. Pseudogenes Pseudogenes exist in two main types: B- Processed pseudogenes are formed through retrotransposition, involving transcription, reverse transcription of mRNA into cDNA, and integration into the genome at a distant location. Processed pseudogenes lack introns and are typically located on different chromosomes from their progenitor genes. Pseudogenes Many gene families contain numerous pseudogenes. Noncoding RNA Many genes encode proteins, but there are also genes that produce noncoding RNAs (ncRNAs), whose functional product is RNA itself. NcRNAs have various roles in the cell, though some functions remain unidentified. Types of ncRNAs include: - tRNAs, rRNAs, RNAs involved in RNA splicing control, and small nucleolar RNAs (snoRNAs) involved in modifying rRNAs. - Long ncRNAs (lncRNAs) play roles in gene regulation, gene silencing, and human disease. - MicroRNAs (miRNAs) are ~22 base-long ncRNAs that regulate protein production by binding to target mRNAs. Pathogenic variants in some ncRNA genes have been associated with various human diseases, including cancer and developmental disorders. Fundamentals of Gene Expression Transcription initiation involves promoters, regulatory elements, and transcription factors determining gene expression patterns. Transcription begins at the transcriptional start site, followed by elongation along the chromosomal DNA, including both introns and exons. Post-transcriptional modifications, including 5′ and 3′ end modifications, occur before RNA splicing. Fundamentals of Gene Expression RNA modification: 5' Cap Addition: The addition of a 7methylguanosine cap to the 5' end of mRNA. This cap structure protects the mRNA from degradation and helps in mRNA export from the nucleus and initiation of translation. 3' Polyadenylation: Addition of a polyadenylate [poly(A)] tail to the 3' end of mRNA. Polyadenylation enhances mRNA stability, facilitates mRNA export from the nucleus, and influences translation efficiency. Fundamentals of Gene Expression RNA modification: RNA Splicing: Removal of intronic sequences and joining of exonic sequences to generate mature mRNA molecules. Alternative splicing allows the production of multiple mRNA isoforms from a single gene, increasing proteomic diversity. Base Modifications: Chemical modifications of individual nucleotides within mRNA, such as methylation or acetylation of adenine, cytosine, guanine, or uracil bases. These modifications can affect mRNA structure, stability, and interactions with RNA-binding proteins. Fundamentals of Gene Expression Errors in any step of this process can lead to inherited disorders, highlighting the importance of each step in gene expression. Epigenetic and Epigenomic Aspects of Gene Expression Epigenetics is the study of mechanisms that leads to changes in gene expression that can be passed from cell to cell and are reversable, but do not involve a change in the sequence of DNA. Epigenetic changes occur through modifications to DNA and associated proteins, such as histones, which can influence gene activity and expression. Epigenetic and Epigenomic Aspects of Gene Expression Epigenetic and Epigenomic Aspects of Gene Expression: DNA Methylation DNA methylation involves modifying cytosine bases by adding a methyl group to the carbon at the fifth position. Methylation of CpG dinucleotides is common and is associated with gene repression during cell differentiation and development. Altered DNA methylation patterns are observed in cancer, including hypomethylation of large genomic segments and hypermethylation at CpG islands. Epigenetic and Epigenomic Aspects of Gene Expression: Histone modification Histone modifications encompass a variety of changes to core histone proteins, including methylation, phosphorylation, and acetylation, among others. Modifications occur predominantly on the N-terminal tails of histones, extending from the core nucleosome. They are thought to influence gene expression by affecting chromatin compaction, accessibility, and signaling of protein complexes. Allelic Imbalance in Gene Expression Traditional assumptions about gene expression levels from homologous alleles have been challenged by the discovery of extensive allelic imbalance. RNA sequencing of cell populations enables quantification of gene expression levels, revealing variability in mRNA abundance. Some genes exhibit allelic imbalance, with RNA products from one allele being more abundant than the other, affecting 5% to 20% of autosomal genes. Allelic imbalance may result from interactions between genome sequence variations and gene regulation mechanisms, such as changes in transcription factor binding or DNA methylation patterns. Allelic Imbalance in Gene Expression Monoallelic Gene Expression Parent-of-origin Imprinting X Chromosome Inactivation