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GENETICS Eemin Chow DEFINITIONS Genetics – the study of genes and heredity. Genes – the genetic material on a chromosome that contains instructions for creating a trait. DEFINITIONS Allele – one of several varieties of a gene. Locus – the location on a chromosome where a gene is located. Every gene has a unique locus on a particular chromosome. Homologous chromosomes – a pair of chromosomes that contains the same genetic information DEFINITIONS Dominant allele – the trait is expressed. Recessive allele – the trait is hidden by the dominant allele; will only be expressed if two recessive alleles are inherited. Homozygous dominant/recessive – the inheritance of two dominant/recessive alleles. Heterozygous – the inheritance of one dominant and one recessive allele. DEFINITIONS Phenotype – the actual expression of a gene Genotype – the actual alleles HISTORY Gregor Mendel is the father of Genetics Was a monk from the 19 th century Studied inheritance in plants Experimented on pea plants Came up with two laws of inheritance MENDEL’S LAW OF INHERITANCE Law of Segregation: the separation of alleles to individual gametes. Each chromosome pair will separate so that each gamete will have one copy of each chromosome. Law of Independent Assortment: the independent assortment of alleles. The migration of homologues within one pair of homologous chromosomes does not influence the migration of homologues or other homologous pairs. MENDEL’S EXPERIMENT He crossed 2 varieties of pea plants to form hybrids. P generation – parent generation F1 generation – first generation offspring F2 generation – second generation offspring Monohybrid cross – experiment where only one trait is observed Dihybrid cross – experiment where two traits are observed INHERITANCE PATTERNS Complete Dominance Monohybrid: traits are expressed when one allele is dominant to a second allele, Dihybrid: when it involves two traits, and the dominant alleles are expressed. Incomplete Dominance the combined expression of two different alleles in the heterozygous condition produces a blending of the individual expressions of the two alleles E.g. Red (R) White (r) Pink (Rr) INHERITANCE PATTERNS Incomplete Dominance the combined expression of two different alleles in the heterozygous condition produces a blending of the individual expressions of the two alleles E.g. Red (R) White (r) Pink (Rr) INHERITANCE PATTERNS Codominance both inherited alleles are completely expressed. Multiple Alleles When a trait has more than 3 possible alleles E.g. Blood type: I A , I B, i INHERITANCE PATTERNS Epistasis when one gene affects the phenotypic expression of a second gene E.g. expression of pigmentation: one gene turns on/off production of pigment, one gene controls color/amount of pigment INHERITANCE PATTERNS Pleiotropy when a single gene has more than one phenotypic expression E.g. Sickle cell disease Polygenic Inheritance the interaction of many genes to shape a single phenotype. E.g. Height, eye color INHERITANCE PATTERNS Link Genes genes that reside on the same chromosome and thus cannot segregate independently because they are physically connected Sex-linked inheritance Inheritance of genes that reside on the sex chromosomes, X and Y E.g. Hemophilia INHERITANCE PATTERNS X-inactivation Occurs in female mammals when one of the two X chromosomes in each cell does not uncoil into chromatin, but remains coiled as a dark, compact body, called a Barr body GENETIC DEFECTS Nondisjunction - the failure of one or more chromosome pairs or chromatids of a single chromosome to properly separate during meiosis or mitosis. Polyploidy - occurs if all of the chromosomes undergo meiotic nondisjunction and produce gametes with twice the number of chromosomes. GENETIC DEFECTS Point mutations - occur when a single nucleotide in the DNA of a gene is incorrect Insertion, deletion, substitution Aneuploidy - a genome with extra or missing chromosomes E.g. Down Syndrome (trisomy 21, three copies of chromosome 21), Turner Syndrome (nondisjunction of sex chromosomes) GENETIC DEFECTS Chromosomal Aberrations - when chromosome segments are changed Duplication - occurs when a chromosome segment is repeated on the same chromosome. Inversion - occurs when chromosome segments are rearranged in reverse orientation on the same chromosome. Translocation - occurs when a segment of a chromosome is moved to another chromosome. MOLECULAR GENETICS Genes are found on DNA, which consists of polymers of nucleotides. DNA (deoxyribose nucleic acid) Adenine, Thymine, Guanine, Cytosine Has a double helix structure MOLECULAR GENETICS RNA (ribose nucleic acid) Adenine, Uracil, Guanine, Cytosine mRNA – provides instructions for assembling amino acids into a polypeptide chain; linear structure tRNA – delivers amino acids to a ribosome for their addition into a polypeptide chain; “clover-leaf ” shape structure rRNA – combines with proteins to form ribosomes; globular structure DNA REPLICATION Before cell division can occur, DNA has to be copied, and the process is called DNA replication. DNA molecules are unzipped into two strands that serve as templates to assemble a new strand. The process is a semiconservative replication because the copied DNA molecule contains a single strand of old DNA and a single strand of new, replicated DNA VOCAB FROM DNA REPLICATION Helicase - unwinds the DNA helix, forming a Y-shaped replication fork. Single-strand binding proteins - attach to each strand of DNA to keep them separate. Topoisomerase – break and rejoin the double helix to unravel twists and prevent the formation of knots. VOCAB FROM DNA REPLICATION DNA polymerase – assembles the new DNA strand in the 3’ -> 5’ direction. A complement strand grows in the antiparallel 5’ -> 3’ direction. Leading strand – the complementary strand that is assembled in the 5’ -> 3’ direction. Okazaki segments – short segments of nucleotides, which are assembled in the 3’ -> 5’ direction, that make up the lagging strand VOCAB FROM DNA REPLICATION DNA ligase – connects okazaki strands to make them into a single complement strand 3’ Primase – initiates a new complementary strand by beginning replication with a short segment of RNA, called RNA RNA Primer primer. Primase 5’ 5’ Every leading strand and every okazaki segment on the lagging strand must begin with an RNA primer. DNA Polymerase III LAGGING STRAND ANIMATION DNA Replication Animation: http://bcs.whfreeman.com/thelifewire/content/chp1 1/1102003.html TELOMERES Ends of DNA containing noncoding, repeating segments– “junk” at the end During replication, the telomeres can’t be replicated. Telomeric DNA prevents genes from being worn away. Telomeres serve as a buffer– they are useless segments that get worn away instead of genes. PROTEIN SYNTHESIS Traits are the end products of metabolic processes regulated by enzymes. Old definition of genes: segments of DNA that codes for a particular enzyme (one-gene-one-enzyme hypothesis). Since many genes code for polypeptides that are not enzymes, there is a new definition. New definition of genes: DNA segments that code for a particular polypeptide (one-gene-one-polypeptide hypothesis). PROTEIN SYNTHESIS Protein synthesis - the process of the production of enzymes and other proteins from DNA. Transcription - RNA molecules are created by using the DNA molecule as a template. RNA processing - modifies the RNA molecule with deletions and additions Translation - the processed RNA molecules are used to assemble amino acids into a polypeptide. RNA Polymerase - the enzyme that transcribes the DNA into RNA TRANSCRIPTION - MRNA Messenger RNA (mRNA) is a single strand of RNA that provides the template used for sequencing amino acids into a polypeptide. A triplet group of three adjacent nucleotides on the mRNA, called a codon, codes for one specific amino acid. There are 64 possible ways that four nucleotides can be arranged in triplet combinations, so there are 64 possible codons. However, there are only 20 amino acids, so some codons code for the same amino acid. TRANSCRIPTION - TRNA Transfer RNA (tRNA) is a short RNA molecule that is used for transporting amino acids to their proper place on the mRNA template. The 3' end of the tRNA attaches to an amino acid. Another portion of the tRNA, specified by a triplet combination of nucleotides, is the anticodon. During translation, the anticodon of the tRNA base pairs with the codon of the mRNA. Wobble allows the anticodon of some tRNA’s to base-pair with more than one kind of codon. TRANSCRIPTION - RRNA Ribosomal RNA (rRNA) molecules are the building blocks of ribosomes. The nucleolus is an assemblage of DNA actively being transcribed into rRNA. Within the nucleolus, various proteins imported from the cytoplasm are assembled with rRNA to form large and small ribosome subunits. Together, the two subunits form a ribosome that coordinates the activities of the mRNA and tRNA during translation. TRANSCRIPTION - RIBOSOMES Ribosomes have three binding sites — one for a tRNA that carries a growing polypeptide chain (P site,) and one for a second tRNA that delivers the next amino acid that will be inserted into the growing polypeptide chain (A site). And an exit site (E site) TRANSCRIPTION - INITIATION Initiation - the RNA polymerase attaches to a promoter region on the DNA and begins to unzip the DNA into two strands. A promoter region for mRNA transcriptions often contains the sequence T–A–T–A called the TATA box. TRANSCRIPTION - ELONGATION Elongation - occurs as the RNA polymerase unzips the DNA and assembles RNA nucleotides using one strand of the DNA as a template. As in DNA replication, elongation of the RNA molecule occurs in the 5' → 3' direction. TRANSCRIPTION - TERMINATION Termination - occurs when the RNA polymerase reaches a special sequence of nucleotides that serve as a termination point. In eukaryotes, the termination region often contains the DNA sequence AAAAAAA. MRNA PROCESSING A 5' cap (–P–P–P–G-5') is added to the 5' end of the mRNA. The 5' cap is a guanine nucleotide with two additional phosphate groups, forming GTP. Capping provides stability to the mRNA and a point of attachment for the small subunit of the ribosome. A poly-A tail (–A–A–A . . . A–A-3') is attached to the 3' end of the mRNA. The tail consists of about 200 adenine nucleotides. It provides stability to the mRNA and also appears to control the movement of the mRNA across the nuclear envelope. MRNA PROCESSING RNA splicing removes nucleotide segments from mRNA. A transcribed DNA segment contains two kinds of sequences: exons, which are sequences that express a code for a polypeptide, and introns, intervening sequences that are noncoding. Before the mRNA moves to the cytoplasm, small nuclear ribonucleoproteins, or snRNP’s, delete the introns and splice the exons. Alternative splicing allows different mRNA’s to be generated from the same RNA transcript. By selectively removing different parts of an RNA transcript, different mRNA’s can be produced, each coding for a different protein product. TRANSLATION Using the mRNA code to create the appropriate protein. Occurs in the cytoplasm/on the rough ER Sequence of 3 nucleotides codes for a particular amino acid = codon 64 different codons Begins with the start codon – AUG Codes for methionine (Met) TRANSLATION Ribosome moves along mRNA in a 5’->3’ direction catalyzing the translation of the mRNA into protein breaks bond between tRNA and amino acid creates a new peptide bond to link it to polypeptide chain TRANSLATION Ribosome is released when a stop codon is reached UAA, UAG, UGA = stop codons (don’t code for any tRNA anticodons) A release factor binds to the mRNA instead Ribosome breaks apart, mRNA and protein are released SUMMARY OF PROTEIN SYNTHESIS Translation/Transcription Animation: http://wwwclass.unl.edu/biochem/gp2/m_biolo gy/animation/gene/gene_a1.html Transcription Animation: http://www.stolaf.edu/people/giann ini/flashanimat/molgenetics/transcr iption.swf Transcription Animation: http://wwwclass.unl.edu/biochem/gp2/m_biolo gy/animation/gene/gene_a2.html Translation Animation: http://www class.unl.edu/biochem/gp2/m_bi ology/animation/gene/gene_a3.h tml MUTATIONS Mutation – any sequence of nucleotides in a DNA molecule that does not exactly match the original DNA molecule from which it was copied. Point mutation is a single nucleotide error A substitution occurs when the DNA sequence contains an incorrect nucleotide in place of the correct nucleotide. A deletion occurs when a nucleotide is omitted from the nucleotide sequence. An insertion occurs when a nucleotide is added to the nucleotide sequence. MUTATIONS - FRAMESHIFT A frameshift mutation occurs as a result of a nucleotide deletion or insertion. Such mutations cause all subsequent nucleotides to be displaced one position. MUTATIONS – SILENT A silent mutation occurs when the new codon still codes for the same amino acid. This occurs most often when the nucleotide substitution results in a change of the last of the three nucleotides in a codon MUTATIONS – MISSENSE A missense mutation occurs when the new codon codes for a new amino acid. The effect can be minor, or it may result in the production of protein that is unable to fold into its proper three-dimensional shape and, therefore, is unable to carry out its normal function. MUTATIONS - NONSENSE A nonsense mutation occurs when the new codon codes for a stop codon. MUTATIONS Mutagens - radiation or chemicals that cause mutations Carcinogens - mutagens that activate uncontrolled cell growth REPAIR Some mechanisms can repair replication errors Proofreading of a newly attached base to the growing replicate strand is carried out by DNA polymerase. DNA polymerase checks to make sure that each newly added nucleotide correctly base pairs with the template strand. If it does not, the nucleotide is removed and replaced with the correct nucleotide. Mismatch repair enzymes repair errors that escape the proofreading ability of DNA polymerase. Excision repair enzymes remove nucleotides damaged by mutagens. The enzymes identify which of the two strands of the DNA contain a damaged nucleotide and then use the complementary strand as a template to repair the error. DNA ORGANIZATION In eukaryotes, DNA is packaged with proteins to form a matrix called chromatin. The DNA is coiled around bundles of eight or nine histone proteins to form DNA-histone complexes called nucleosomes. During cell division, DNA is compactly organized into chromosomes. When the cell is not dividing, the DNA is arranged as either of two types of chromatin, as follows. Euchromatin describes regions where the DNA is loosely bound to nucleosomes. DNA in these regions is actively being transcribed. Heterochromatin represents areas where the nucleosomes are more tightly compacted and where DNA is inactive. REGULATION OF GENE EXPRESSION Gene expression = transcribing and translating the gene Regulation allows an organism to selectively transcribe and translate only the genes it needs to. Genes expressed depend on the type of cell the particular needs of the cell at that time. REGULATION OF GENE EXPRESSION Operon - a unit of DNA that controls the transcription of a gene. The promoter region is a sequence of DNA to which the RNA polymerase attaches to begin transcription. The operator region can block the action of the RNA polymerase if this region is occupied by a repressor protein. REGULATION OF GENE EXPRESSION The structural genes contain DNA sequences that code for several related enzymes that direct the production of some particular end product. A regulatory gene, lying outside the operon region, produces repressor proteins, substances that occupy the operator region and block the action of RNA polymerase. Other regulatory genes produce activator proteins that assist the attachment of RNA polymerase to the promoter region. LAC OPERON Inducible operon - operon is usually “OFF” but can be stimulated/activated The lac operon in E. coli controls the breakdown of lactose. A regulatory gene produces an active repressor that binds to the operator region. LAC OPERON When the operator region is occupied by the repressor, RNA polymerase is unable to transcribe several structural genes that code for enzymes that control the uptake and subsequent breakdown of lactose. When lactose is available, however, some of the lactose (in a converted form) combines with the repressor to make it inactive. When the repressor is inactivated, RNA polymerase is able to transcribe the genes that code for the enzymes that break down lactose. LAC OPERON ANIMATION Lac Operon Animation: http://bcs.whfreeman.com/thelifewire/con tent/chp13/1302001.html POSITIVE GENE REGULATION In the lac operon there are other molecules to further stimulate transcription. Lactose will only be digested for energy when there isn’t much glucose around When glucose levels are low, level of cAMP molecule builds up POSITIVE GENE REGULATION CAP – a regulatory protein that binds to cAMP CAP is inactive unless cAMP binds to it If there isn’t much glucose high levels of cAMP CAP and cAMP bind CAP can bind to the promoter stimulates RNA Polymerase to bind POSITIVE GENE REGULATION When glucose levels rise again, cAMP levels will drop no longer bound to CAP CAP can’t bind to promoter transcription slows down The lac operon is controlled on 2 levels: Presence of lactose determines if transcription can occur CAP in the active form determines how fast transcription occurs TRP OPERON Repressible Operon - Operon that is usually “ON” but can be inhibited The trp operon in E. coli produces enzymes for the synthesis of the amino acid tryptophan. A regulatory gene produces an inactive repressor that does not bind to the operator. As a result, the RNA polymerase proceeds to transcribe the structural genes necessary to produce enzymes that synthesize tryptophan. TRP OPERON When tryptophan is available to E. coli from the surrounding environment, the bacterium no longer needs to manufacture its own tryptophan. In this case, rising levels of tryptophan induce some tryptophan to react with the inactive repressor and make it active. Here tryptophan is acting as a corepressor. The active repressor now binds to the operator region, which, in turn, prevents the transcription of the structural genes. ANIMATION Trp Operon Animation: http://bcs.whfreeman.com/thelifewire/conte nt/chp13/1302002.html MECHANISMS OF GENE EXPRESSION IN EUKARYOTES Regulatory proteins, repressors and activators, operate similarly to those in prokaryotes, influencing how readily RNA polymerase will attach to a promoter region. Nucleosome packing influences whether a section of DNA will be transcribed. DNA segments are tightly packed by methylation (addition of methyl groups) of histones, making transcription more difficult. In contrast, acetylation (addition of acetyl groups) of histones allows uncoiling and transcription of specific DNA regions. MECHANISMS OF GENE EXPRESSION IN EUKARYOTES RNA interference occurs when short interfering RNAs (siRNAs) block mRNA transcription or translation or degrade existing mRNA. Under certain conditions, an RNA molecule will fold back and base-pair with itself, forming dsRNA. An enzyme then cuts the dsRNA into short pieces (siRNAs), which then base-pair to complementary DNA regions—those regions that made the original RNA molecule—preventing further transcription of that gene. The siRNAs also inactivate mRNA already produced by base pairing with it. In other cases, siRNAs combine with enzymes to degrade existing mRNAs with complementary sequences.