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Introduction to Genetics and Genomics Christina Sax Maryland University of Integrative Health #MUIH @MUIHealth @CMSax Outline 1. 2. 3. 4. 5. Cells, DNA, Chromosomes Genes and Gene Expression Gene Regulation Human Genetics Genetic Variation Part 1: Cells, DNA, Chromosomes Cells, DNA, Chromosomes • Humans composed of eukaryotic cells • Eukaryotic – animal cells • Prokaryotic – bacterial cells • Every eukaryotic cell contains a nucleus • Nucleus contains genetic information (chromosomes, DNA, and genes) • Cells contain the same complete set of genetic information Cells • Basic building block of living organisms • Adult human body has 10 to 100 trillion cells • Membrane: semi-permeable, regulatory barrier • Ribosomes and Endoplasmic Reticulum: protein production • Nucleus: houses genetic information, site of DNA & RNA production DNA and Chromosomes • Human cells • 46 chromosomes • 46 pieces of DNA • DNA - Deoxyribonucleic Acid • A type of nucleic acid (DNA & RNA) • Molecule that carries genetic information and instructions in living cells • Chromosome • Physical structure of compacted DNA • Genome – all the DNA in a cell or organism • Genomics – study of structure, function, analysis, mapping of the genome https://www.youtube.com/watch?v=dKubyIRiN84 Why twist & compact? • Space: total length of DNA a single cell is 6 feet • Protection from tangles and breakage DNA Double Helix • Double helix - structure of the DNA molecule • DNA molecule consists of 2 strands that wind around each other like a twisted ladder • 3 primary components • Nucleotides • Sugar phosphate backbone • Hydrogen bonds Nucleotides • Basic building blocks of nucleic acids (DNA & RNA) • 4 different nucleotides in DNA • • • • A – adenine C – cytosine G – guanine T - thymine • Nucleotides are molecules with 3 distinct parts • Phosphate group (common) • Sugar (varies between DNA & RNA) • Nitrogenous base (varies between nucleotide) Nucleotides Nucleotides On one side of DNA ladder nucleotides boned together through sugar and phosphate groups DNA is a polymer made of long chains of nucleotides bonded together Sugar-Phosphate Backbone • Each strand has a backbone made of alternating groups of sugar (deoxyribose) and phosphate groups • Sugar-phosphate backbone is portion of DNA double helix that provides structural support to the molecule • The order of nucleotides in a DNA molecule has meaning • The order of nucleotides = genetic instructions Nucleotide Base Pairing • Two strands of DNA are held in close proximity by weak hydrogen bonds • Weak bonds allow two strands to separate from one another for important processes • Hydrogen bonds form between nucleotide bases on each side of DNA ladder • Human genome has: • 6 billion individual nucleotides • 3 billion pairs of nucleotide base pairs Nucleotide Base Pairing Rules • Hydrogen bonds only form between certain pairs of nucleotides • Size – uniform width of rungs of the ladder • Purine (large) – Pyrimidine (small) • Chemical alignment for hydrogen bonding • Adenine (A) – Thymine (T) • Cytosine (C) – Guanine (G) • Result: stability & flexibility Review and Questions • What is the relationship between DNA and chromosomes? • What is the overall structure of DNA? • What are the nucleotide base pairing rules? • Why are the nucleotide base pairing rules important? • Other ???? Part 2: Genes & Gene Expression Genes • Basic physical and functional unit of heredity • Defined segments of DNA • Chromosome = book • Genes = chapters • Vary in size from a few hundred DNA nucleotides long to more than 2 million nucleotides long • Human Genome Project estimates humans have between 20,000 and 25,000 genes per cell Genetic Coding • Discrete instructions coded in DNA • The order of nucleotides in a DNA molecule has meaning • The order of nucleotides = the genetic instructions for how to make specific proteins Translating the Code The Central Dogma: DNA to RNA to Proteins • Two processes to use transfer information and use directions coded in DNA to make proteins • Transcription: use info DNA to make RNA • Translation: use info in RNA to make protein RNA Structure • Similar to DNA • Nucleic acid molecule • Nucleotide building blocks • Nucleotides bonded together through sugar and phosphate groups • Different from DNA • Single Strand • Nucleotide differences • Oxy (-OH) group in sugar • Uracil (U) instead of Thymine (T) Transcription • Transfer information stored in DNA to storage in RNA • Messenger RNA (mRNA) • Information stored in order of nucleotides in both DNA and RNA • Use DNA as a template to make RNA – the order of nucleotides in DNA determines the order of nucleotides in RNA DNA A G A T C G G Coding Strand mRNA T C T A G C C A G A U C G G Template Strand RNA Nucleotide Rules A–U C-G Transcription: Major Players GENE Upstream Promoter of Gene Region Coding Region Promoter Region: Nucleotide sequences that attract proteins and enzymes that synthesize mRNA Terminator Downstream Region of Gene Terminator Region: Nucleotide sequences that cause RNA polymerase to disconnect from DNA; mRNA synthesis stops Transcription Process Gene expression profiling measures amount of mRNA produced, using PCR, microarray, DNA chip technology Translation: RNA to Protein • Use information stored in RNA to make specific proteins • Information stored in order of nucleotides in RNA • The order of nucleotides in RNA determines the order of amino acid subunits in the protein DNA A G A T C G G Coding Strand mRNA T C T A G C C Template Strand A G A U C G G Protein Protein Structure • Proteins are large complex molecules • Built from amino acids subunits, bonded together in long chains • 20 different types of amino acids Translation: Cracking the Code • mRNA interacts with ribosome complex • Ribosome "reads" the sequence of nucleotides in mRNA • Each sequence of 3 nucleotides is called a codon • Each unique codon indicates that a particular amino acid should be added next to the growing protein molecule Translation: Cracking the Code mRNA CUUAGGCUG Protein Leucine Leucine Arginine Translation Process Review and Questions • • • • • • • • • • What is a gene? What kind of information is coded in DNA? How is information coded in DNA? What is the overall structure of RNA? What is the overall structure of a gene? What is the role of a gene’s promoter region? What activities occur during transcription? What is the overall structure of protein? What activities occur during translation? How is the order of amino acids in a protein determined? • Other ???? Part 3: Gene Regulation Gene Expression and Regulation • Gene Expression - process by which information from a gene is used in the synthesis of a functional gene product • Regulation of Gene Expression - mechanisms used by cells to increase or decrease the production of specific gene products • When combined, determine the characteristics of cells and organisms • Together, determine the complement of proteins and relative amounts of proteins in cells and organisms • Proteins do most of the work in cells - required for the structure, function, and regulation of cells, tissues, organs Cell Differentiation • All cells in the body contain the same complete set of genes • Some genes are active (and make protein) in all cell types • Some genes are only active in specific cell types, and only make protein in that cell type • Each cell expresses only a fraction of its genes • Unique sets of proteins differentiates cell types from one another and gives them their unique characteristics & functions MUSCLE NEURON Differential Gene Expression MUSCLE Ferritin (stores & release iron in a controlled manner) On Myosin (fibrous & contractile) Off Dopamine (transmits signals) Off On MUSCLE NEURON On On Off Off On Protein Function determined by Structure The order of amino acids determines each protein’s unique 3D structure, shape, and specific function Gene Regulation Genes differentially turned on and off … • During various stages of organismal development • During various stages of a cell’s lifecycle • In response to environmental changes (e.g. metabolism, infection) • As a result of variation and modification of a gene’s nucleotide sequence • As a result of modification of transcriptional regulatory proteins Gene Regulation Gene Regulation Epigenetics Genetic Variation Epigenetics Common minor changes in an Changes in an organism organism caused by caused by modification of modification of the gene gene expression For example, single nucleotide polymorphisms Change in protein structure Change in production of and function protein Nutritional Genomics Nutrigenomics • NUTRITIONAL GENETICS: combination of nutrigenomics and nutrigenetics • NUTRIGENOMICS: effects of nutrients on genome, gene expression, gene regulation, proteome, and metabolome • NUTRIGENETICS: identifies how genetic makeup of a particular individual coordinates his or her response to various dietary nutrients Nutrigenetics Review and Questions • What is gene expression? • What is gene regulation? • What is the general role of proteins in cells and organisms? • How do DNA and proteins contribute to cell differentiation? • What are the factors that regulate the expression of a gene? • What is epigenetics? How does it relate to DNA? • What is neutrogenomics? How does is relate to DNA? • Other ???? Part 4: Human Genetics Human Chromosomes • 46 chromosomes per cell • 23 pairs of chromosomes per cell • 22 pairs autosomal chromosomes • 1 “pair” sex chromosomes (X and Y) • 1 chromosome in each pair inherited from mother, 1 from father • Since there are genes on each chromosome, each cell has 2 copies of each gene Genotype and Phenotype • Genotype – the genetic makeup of an organism • Phenotype – observable characteristics of an individual resulting from (physical & chemical): • Expression of its genes and the production of proteins • Interaction of genotype and proteins with environment Inherited Human Traits (Phenotypes) • Single gene traits • Mendelian inheritance • Dominant traits • Recessive traits • Autosomal and X-linked traits • Complex traits • Many genes involved in determining the trait • Polygenic, multifactorial • Specific degree of expression and resulting phenotype difficult to predict Autosomal Dominant Traits • Require only one copy of a gene to express the trait • Two alleles (variants) for the gene • A: autosomal dominant • a: autosomal recessive Affected Parent A a Unaffected Parent a a Aa Aa aa aa Autosomal Recessive Traits • Recessive traits require two copies of a gene to express the trait • A 'carrier' has only one copy of the gene for the recessive trait, so the carrier does not express the trait • Two alleles (variants) for the gene • R: autosomal dominant • r: autosomal recessive Carrier Father R r Carrier Mother R r RR Rr Rr rr Review and Questions • What is the composition of chromosomes in human cells? • What are genotype and phenotype? How are they related to one another? • How are genes inherited? • Other ???? Part 5: Genetic Variation Genetic Variation • Human genome is 99.9% identical among individuals • Most genes have small sequence differences that vary among individuals – polymorphisms • ALLELES - Alternative forms of a gene with small differences in their sequence of DNA bases. • SINGLE NUCLEOTIDE POLYMORPHISMS (SNPs) - Single nucleotide change at a specific location in DNA • These small differences in DNA result in small differences in the proteins made by cells, and contribute to each person’s unique physical features. SNPs • Single nucleotide change at a specific location in DNA • Most simple form of genetic polymorphism • Represent 90% of human polymorphisms • Four possible SNPs per spot in DNA • Each variant (version) = Allele • Occurs 1 in every 100-300 nucleotides Mutations • Changes in the structure of DNA, resulting in a variant form that may be transmitted to subsequent generations • Types of changes • Alteration of a single nucleotide • Deletion, insertion, rearrangement of larger sections of DNA • Result of changes • • • • Changes to the production, structure, function of the coded protein Non viability Disease Normal variation • SNPs vs Single Nucleotide Mutations • SNPs present in 1% or more of population • Mutations present in <1% of population Types of SNPs and Consequences Non-Coding Region of DNA (in between genes) Coding Region of DNA (in the gene) Non-Synonymous SNP Missense SNP Change of codon results in a change of 1 amino acid in the protein Synonymous SNP Silent change. Change of codon, but no change of amino acid in the protein Nonsense SNP Creates a stop codon in the gene and results in premature truncation of the protein (incomplete protein made) SNPs and Codon Changes (example) SNP Variant Variant 1 Variant 2 (synonymous SNP) Codon UGU UGC Amino Acid Cysteine Cysteine Variant 3 (missense SNP) Variant 4 (nonsense SNP) UGC UGC Tryptophan Stop codon SNPs and Protein Changes • SNPs can change the structure and function of protein … can change cell and organismal function SNP variant 1 protein SNP variant 2 protein MTHFR Gene and Enzyme MTHFR = methylene tetrahydrofolate reductase enzyme (rate-limiting enzyme in methyl cycle) Supports: • Processing of dietary folic acid • Production of DNA, RNA, proteins, lipids • DNA methylation DNA Methylation • Methyl groups added to adenine (A) and cytosine (C) nucleotides in DNA • DNA methylation typically represses gene expression – blocks mRNA and protein production Epigenetics Epigenetics Changes in an organism caused by modification of gene expression Change in production of protein SNP - MTHFR 677T GCC = Alanine Alanine Valine GTC = Valine thermolabile MTHFR enzyme MTHFR 677T SNP Impaired function of MTHFR leads to blocks completion of folate cycle and entry into methylation cycle … • Sensitive to folic acid intake • Blocks DNA, RNA, protein, lipid synthesis • Blocks DNA methylation Genetic Variation Common minor changes in an organism caused by modification of the gene Change in protein structure and function Nutritional Genomics Nutrigenomics • NUTRITIONAL GENETICS: combination of nutrigenomics and nutrigenetics • NUTRIGENOMICS: effects of nutrients on genome, gene expression, gene regulation, proteome, and metabolome • NUTRIGENETICS: identifies how genetic makeup of a particular individual coordinates his or her response to various dietary nutrients Nutrigenetics MTHFR and Methylation MTHFR MTHFR 677T SNP Methylation cycle proceeds Methylation cycle slows DNA methylation occurs DNA methylation occurs at a lesser rate Gene expression repressed Gene expression more active Specific set of proteins made/not made New and different set of proteins made Genetic Variation vs Epigenetics MTHFR Epigenetics Changes in an organism caused by modification of gene expression Change in production of protein MTHFR 677T SNP Methylation cycle proceeds Methylation cycle slows DNA methylation occurs DNA methylation occurs at a lesser rate Gene expression repressed Gene expression more active Specific set of proteins made/not made New and different set of proteins made Genetic Variation Common minor changes in an organism caused by modification of the gene Change in protein structure and function Review and Questions • What are single nucleotide polymorphisms (SNPs)? • What is their impact on genetic variation in the human population? • What is their potential impact on protein production, structure, and function? • What is the role of DNA methylation in cells? • How is DNA methylation and the MTHFR gene/protein an example of both epigenetics and genetic variation? • How is MTHFR an example of nutrigenetics? • Other ????