Genetics test 3

wilms tumor

malignant tumor of the kidney occurring in childhood

Cancer in some form strikes more than

1/3 the population in their lifetime

CF gene has more than

1900 different mutations have been identified including deletions, nucleotide substitutions, and frameshift mutations

trisomy 21 - downs syndrome

20 times more likely to get leukemia.

cancer accounts for `

20% of all deaths

a model for colon cancer

5 to seven steps

heritable predisposition

5% of all patients with cancer

spontaneous mutations

95% of all patients with cancer

Peptide bond

A covalent chemical link between the carboxyl group of one amino acid and the amino group of another amino acid

A gene is transcribed from ________ to ________, and translated into a series of ________.

A gene is transcribed from DNA to MRNA, and translated into a series of codons.

Polypeptide

A molecule made of amino acids joined together by peptide bonds

proto-oncogene

A normal cellular gene corresponding to an oncogene; a gene with a potential to cause cancer but that requires some alteration to become an oncogene.

A polypeptide is the product of a single ________.

A polypeptide is the product of a single gene.

transcription factor

A regulatory protein that binds to DNA and affects transcription of specific genes.

microsatellite

A set of short repeated DNA sequences at a particular locus on a chromosome, which vary in number in different individuals and so can be used for genetic fingerprinting - repeated a whole bunch in one place. bc they're short and repeated, it is a very good place for mismatching to occur. people that have mutations in a repair gene, the repeats get bigger.

Messenger RNA (mRNA)

A single-stranded complementary copy of the DNA sequence in a gene

E2F

A transcription factor required for the synthesis of components that are required for S phase. If Rb inhibits E2F at promoter, then don't get expression of replication genes.

philadelphia chromosome

Abnormal chromosome produced by translocation between the long arms of chromosomes 9 and 22 Causes chronic myelogenous leukemia (CML) Chromosome 9 gives some to chromosome 22

prader willi - 80% will have deletion

Almond eyes, obesity, hyperphagia - think - long arm of 15Q - inherited from dad

compound heterozygotes

An individual with two different recessive alleles at a locus that results in a recessive phenotype - two different disease alleles. 2 different mutant alleles.

lynch syndrome

Aut dom trait caused by mutations in one of four, MSH2 & MLH1 - MSH6 PMS2 - genomic instability of microsatellite DNA sequences - destabalizes the genome

AUG

methionine - start codon

Biochemical reactions in the cell are linked together to form metabolic pathways A chemical compound can be the product of one enzymatic reaction and the substrate for the next reaction in a metabolic pathway Mutations that block one reaction in a pathway can produce mutant phenotypes in several ways

Cancer Is a Genetic Disorder Cancer in some form strikes more than one third of the population in their lifetime The primary risk factor for cancer is age Cancer accounts for more than 20% of all deaths In developed countries, cancer is responsible for more than 10% of the total cost of medical care Cancer is invariably fatal if it is not treated Cancer Is a Genetic Disorder Early diagnosis and early treatment are vital Identification of people at increased risk of cancer before its development is an important objective of cancer research Cancer is a genetic disease Inherited - the initial cancer-causing mutation is inherited through the germline (usually show a dominant pattern of inheritance) Sporadic - cancer that originates from the accumulation of mutations in a single somatic cell Cancers are Malignant Tumors Neoplasia is a disease process characterized by uncontrolled cellular proliferation leading to the growth of a tumor (neoplasm) Benign tumors remain in their site of origin and do not invade other tissues For a tumor to be cancer, it must also be malignant, which means it is capable of spreading or metastasizing to other locations Two Characteristics of Cancer Uncontrolled cell division The ability of cancer cells to spread to other parts of the body (metastasize) Cancer Cells Have Abnormal Shapes Cancer cells have uncontrolled cell division and ability to metastasize Mutations Cause Cancer Cancer is a genetic disorder that acts at a cellular level Heritable predisposition (~5% of all patients with cancer) Spontaneous mutations (~95% of all patients with cancer). Environmental and behavioral factors Cancer Begins in a Single Cell Cancer cells are clonal descendants from one mutant cell The cell accumulates a number of specific mutations over a long period of time Age is the primary risk factor for cancer Cancer cells escape control of the cell cycle and begin uncontrolled division Mutations continue to accumulate Cancer Cells are Invasive Metastasis A process by which cells detach from the primary tumor and move to other sites in the body, forming new malignant tumors The ability to invade new tissues results from new mutations in cancer cells Metastasis Inherited Susceptibility and Sporadic Cancers Hereditary cancer Inherited mutant gene causes a predisposition to cancer Mutation is carried in all cells One or more additional mutations accumulate Sporadic cancer Spontaneous mutant gene causes a predisposition to cancer Mutation occurs in a single somatic cell One or more additional mutations accumulate in the same somatic cell Heritable Predispositions to Cancer Cells Acquire Mutations Over Time Keep In Mind Cancer can be caused by an inherited susceptibility or a sporadic event Cancer Can Involve the Cell Cycle Study of two classes of genes has established a relationship between cancer, regulation of cell growth and division, and the cell cycle Tumor suppressor genes normally turn off or decrease the rate of cell division Proto-oncogenes normally turn on or increase the rate of cell division Tumor Suppressor Genes Tumor suppressor genes Genes encoding proteins that suppress cell division and regulate the cell cycle These gene products act at control points in the cell cycle, at G1/S or G2/M Deletion or inactivation of these products cause cells to divide continuously Recessive mutations in tumor suppressor genes cause cancer Oncogenes Proto-oncogenes Genes that initiate or maintain cell division Dominant mutations in proto-oncogenes cause cancer; the mutant proto-oncogene is referred to as an oncogene Oncogenes Mutant genes that induce or continue uncontrolled cell proliferation The Eukaryotic Cell Cycle Retinoblastoma: Mutation of a Tumor Suppressor Gene Retinoblastoma Retina - layer of nerve tissue in back of eye that is sensitive to light A malignant tumor of the eye arising in retinoblasts (embryonic retinal cells that disappear at about 2 years of age) Because mature retinal cells do not transform into tumors, this tumor usually occurs only in children Usually diagnosed between 1 to 3 years of age Caused by mutations in the RB1 gene on chromosome 13 Retinoblastoma Two Types of Retinoblastoma Familial retinoblastoma (hereditary) Individuals inherit one mutant copy of RB1 gene and one normal copy of the RB1 gene Normal copy of RB1 gene acquires a spontaneous mutation 85% to 95% chance of developing the disease Usually involves both eyes and occurs earlier in life Sporadic retinoblastoma Mutations of both copies of RB1 gene occur in a single cell Usually involves one eye and occurs later in life Hereditary and Sporadic Retinoblastoma Comparison of Hereditary and Sporadic Forms of Cancer The RB1 Gene Encodes pRB Protein The tumor-suppressor protein pRB controls the G1/S transition in the cell cycle Without pRB, cell division is uncontrolled The Eukaryotic Cell Cycle pRB Keep In Mind Cancer cells bypass cell cycle checkpoints and divide continuously How Do Proto-Oncogenes Become Oncogenes? Oncogenes are permanently switched on proto-oncogenes that cause uncontrolled cell division Mutations can produce an altered gene product Mutations can overproduce a normal gene product Mutations can increase the number of copies of a normal gene The ras Proto-Oncogene Cancer Can Affect DNA Repair Systems Many basic properties of cancer result from the inability of cancer cells to repair damage to DNA high rates of mutation chromosomal abnormalities genomic instability DNA repair genes are now recognized as a class of cancer-related genes along with tumor suppressor genes and proto-oncogenes Breast Cancer Breast cancer is the most common form of cancer in women in the U.S.; 12% of all women will get breast cancer in their lifetime More than 1 in 4 cancers diagnosed in U.S. women are breast cancer Breast cancer incidence and death rates generally increase with age; median age at diagnosis is 61 years Breast cancer is the leading cause of cancer death in women between the ages of 15 and 54 Breast Cancer Early detection of breast cancer through monthly breast self-exam (beginning at age 20) and yearly mammography (beginning at age 40), offers the best chance for survival About 90% of all breast cancers are spontaneous and multifactorial in nature Of the approximately 10% of breast cancers that are hereditary, most are caused by mutations in the BRCA1 gene or the BRCA2 gene Genetic Predisposition to Cancer:BRCA1 and BRCA2 Genes Mutations in BRCA1 and BRCA2 genes predispose women to breast and ovarian cancer BRCA1 and BRCA2 proteins maintain genomic integrity by regulating DNA repair BRCA1 and BRCA2 are DNA Repair Genes Mutations in the BRCA1 or BRCA2 genes are inherited as autosomal dominant mutations, but mutations in both copies of BRCA1 or BRCA2 are required to cause cancer Two mutant alleles of BRCA1 increase the risk of breast and ovarian cancer in females, and prostate cancer in males Two mutant alleles of BRCA2 increase the risk of breast and ovarian cancer in females, and breast and prostate cancer in males Mutant forms of the BRCA1 and BRCA2 proteins are unable to repair DNA Mutations accumulate; cell become cancerous Colon Cancer:A Genetic Model for Cancer Cancer is a multistep process that requires a number of specific mutations Study of colon cancer provides insight into the number and order of steps involved in transforming normal cells into cancer cells Colon and Rectal Cancer in the US Two Types of Heritable Colon Cancer Colon cancer starts as a benign tumor that later becomes malignant Six or more mutations required to initiate cancer There are two pathways to colon cancer related to genetic predispositions Familial adenomatous polyposis (FAP) Lynch syndrome (formerly called hereditary nonpolyposis colon cancer, HNPCC) FAP Familial adenomatous polyposis (FAP) An autosomal dominant trait caused by a mutation in the adenomatous polyposis coli (APC) gene Both alleles of APC must be inactivated for cancer to develop Development of hundreds to thousands of polyps (benign growths in the colon) Polyps often develop into malignant growths and cause cancer of the colon and/or rectum, but only after a cell acquires mutations in numerous additional genes Polyps Polyps are growths attached to the substrate by small stalks In the colon they are precursors to colon cancer A Model For Colon Cancer Five to Seven Steps Required for Familial Adenomatous Polyposis (FAP) Colon Cancer Mutation in the APC gene (first step for FAP) Mutation of one copy of the k-ras proto-oncogene in a polyp cell transforms the polyp into an adenoma Mutations in both alleles of any of several downstream genes, including DCC, leads to formation of late-stage adenomas Mutations in both alleles of the p53 gene cause the late-stage adenoma to become cancerous Number of Mutations in Some Cancers Lynch syndrome (formerly HNPCC) Lynch syndrome An autosomal dominant trait caused by mutations in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) Subsequent somatic loss-of-function of the second normal copy of the gene is required for cancer to develop Associated with genomic instability of microsatellite DNA sequences and a form of colon cancer that develops with very few polyps, but each with a high probability of becoming cancerous Lynch SyndromeDestabilizes the Genome Proteins encoded by DNA mismatch repair genes fix errors made during DNA replication Mutations in DNA mismatch repair genes destabilize the genome, generating a cascade of mutations in DNA microsatellites Microsatellites are DNA sequences, 2 to 9 nucleotides long, that are repeated thousands of times and located on many chromosomes Mutations in microsatellites lead to mutations in neighboring genes Lynch Syndrome Predisposes Patients to Many Cancers Lynch syndrome is the most common form of inherited colorectal and endometrial cancers Patients with Lynch syndrome are also at increased risk for cancers of the ovary, stomach, small intestine, pancreas, upper urinary tract, hepatobiliary tract, brain, skin, and prostate Gatekeeper Genes and Caretaker Genes Gatekeeper genes Genes that regulate cell growth and passage through the cell cycle; for example, tumor suppressor genes and many proto-oncogenes APC is an example Caretaker genes Genes that help maintain the integrity of the genome; for example, DNA repair genes MSH2 and MLH1 are examples Genetic Disorders Caused by Mutations in DNA Repair Genes Keep In Mind Colon cancer is a multistep process that involves oncogenes and mutant tumor suppressor genes Chromosome Changes, Hybrid Genes, and Cancer Changes in number and structure of chromosomes are common in cancer cells Disorders Associated With Cancer Some disorders, such as Down syndrome, are associated with high rates of cancer Down syndrome individuals have an increased risk of leukemia and have defects in their immune system Chromosome Rearrangements Can Be Related to Cancers Some cancers, such as chronic myelogenous leukemia (CML), are caused by translocation events, creating hybrid genes that activate cell division Philadelphia chromosome Other forms of cancer are also associated with specific chromosomal abnormalities Myeloblastic leukemia, Burkitt's lymphoma, multiple myeloma Translocations Associated with Cancers Translocations and Hybrid Genes Can Lead to Leukemia Many proto-oncogenes are located at or close to the breakpoints of chromosomal translocations involved with specific forms of leukemia In CML, the C-ABL gene (chromosome 9) is connected to the BCR gene (chromosome 22) The hybrid gene encodes an abnormal protein that signals CML cells to divide The Philadelphia Chromosome and CML Philadelphia chromosome Abnormal chromosome produced by translocation between the long arms of chromosomes 9 and 22 Causes chronic myelogenous leukemia (CML) s Formation of Hybrid Gene in CML New Cancer Drugs are Being Designed Gleevec inactivates the BCR-ABL protein; cancer cell stops dividing Keep In Mind Several types of translocations associated with cancer create hybrid genes Epigenetics and Cancer Epigenetic changes to DNA can alter gene expression and contribute to cancer Abnormal DNA methylation is associated with many types of cancers Cancer and the Environment Epidemiology The study of factors that control the presence, absence, or frequency of a disease Provides statistical correlation between the environment and diseases such as cancer Many cancers are environmentally induced What are Some Environmental Factors For Cancer? Exposure to certain materials and chemicals Occupational exposure poses a cancer risk to workers in a number of industries Widespread dissemination poses a potentially large risk to the general population What are Some Environmental Factors For Cancer? Viruses have been determined to be the cause of a few cancers The Epstein-Barr virus has been linked with Burkitt's lymphoma The Hepatitis B and C viruses have been linked with liver cancer in people with chronic infections Papilloma viruses have been linked with cervical cancer (HPV16 and HPV18) Behavior is an Environmental Factor Social behavior contributes to approximately 50% of all cancer cases in the United States Smoking accounts for 75-85% of all cases of lung cancer Smoking accounts for 30% of all cancer deaths Skin cancer cases related to UV exposure are increasing (one million new cases per year in the United States) Skin Cancer Skin cancer is the most common form of cancer in the US, accounting for half of all cancer cases There has been more than a tenfold increase in skin cancer since 1967; skin cancer cases are increasing at a rate of 3% to 5% per year Ozone depletion in the atmosphere contributes to increased levels of UV radiation Skin Cancer Rates Keep In Mind Diet and behavior are two major factors in cancer prevention

colon cancer

Cancer of the large intestines

oncogene

Cancer-causing genes that are formed due to mutations

Processing and Splicing pre-mRNA to mRNA

Cap A modified base (guanine nucleotide) attached to the 5' end of eukaryotic mRNA molecules during RNA processing Poly-A tail A string of 30-100 adenine (A) nucleotides added to the 3'end of mRNA molecules during RNA processing Splicing The introns are spliced out to produce mature mRNA

COLON CANCER is a

multistep process that involves oncogenes and mutant tumor suppressor genes

cancer is caused by

mutation

frameshift mutation

mutation that shifts the "reading" frame of the genetic message by inserting or deleting a nucleotide

germline mutation

mutations occur in germ cell that participates in fertilization

imprinting means

non functioning

translation

Conversion of information encoded in the nucleotide sequence of an mRNA molecule into the linear sequence of amino acids in a protein

thiamine dimer

D/t UV light; 2 adjacent thiamines connect. Dimer changes structure of DNA and leads to problems during DNA replication.

Introns

DNA sequences present in some genes that are transcribed, but are removed during processing and therefore are not present in mature mRNA

Exons

DNA sequences that are transcribed, joined with other exons in mRNA processing, and translated into the amino acid sequence of a protein

The function of a protein is ultimately determined by its ________.

DNA-controlled primary structure

Enzyme A protein that catalyzes chemical reactions in the body without being altered itself

Enzyme A protein that catalyzes chemical reactions in the body without being altered itself Substrate The specific compound acted on by an enzyme Product The specific compound that results from enzymatic action

Proteins Are the Link Between Genes and the Phenotype Proteins are the end products of the transcription and translation of genes Proteins link genes and phenotype Involving cell structure, metabolic reactions, hormonal responses, cell-to-cell signaling systems, and the immune system Keep In Mind Phenotypes are the "visible" end product of a chain of events that starts with the gene, the mRNA, and the protein product Other Metabolic Disorders in the Phenylalanine Pathway The mutation that results in PKU is only one of several genetic disorders caused by the mutation of genes in the phenylalanine pathway Others include defects of thyroid hormone, albinism, and alkaptonuria, the disease investigated by Garrod PKU and Other Disorders of the Metabolic Pathways of Phenylalanine Genes and Enzymes of Carbohydrate Metabolism Mutations in genes encoding enzymes can affect the metabolic pathways of other biological molecules, including carbohydrates Galactosemia is a genetic disorder caused by lack of an enzyme in carbohydrate metabolism Lactose intolerance is a genetic disorder caused by low levels of an enzyme in carbohydrate metabolism Galactosemia and Inheritance Galactosemia is an autosomal recessive disorder with a frequency of 1 in 57,000 births Galactosemia is a multiple-allele gene system Normal allele G+, recessive allele g, and the Duarte allele GD with half normal enzyme activity Multiple Alleles of Galactosemia Lactose Intolerance Levels of lactase (the enzyme that digests lactose) drop off during middle to late childhood Lactose intolerance is a genetic variation in lactase levels that affects millions of adults worldwide Lactose intolerance is inherited as a recessive trait that causes a decline in adult lactase levels Defects in Transport Proteins: Hemoglobin (HbA) Defects in Hemoglobin:Sickle Cell Anemia Studies by Linus Pauling and James Neel (1949) concluded that: People with sickle cell anemia have an abnormal hemoglobin protein Sickle cell anemia is inherited as an autosomal recessive disorder A mutant gene involved in the synthesis of hemoglobin causes sickle cell anemia Vernon Ingram (1959) showed that sickle cell anemia is caused by single amino acid change in the beta globin polypeptide Sickle Cell Anemia: An Autosomal Recessive Trait with Many Symptoms Sickle Cell Anemia: An Autosomal Recessive Trait with Many Symptoms Sickle Cell Anemia: Abnormal Hemoglobin Polymerization of beta globin to form long fibers A Single Amino Acid Substitution in the Beta Globin Polypeptide in HbS Studies of Sickle Cell Anemia Sickle cell anemia was the first example showing that a genetic disorder can be caused by a defect in a single molecule First direct proof that mutations in DNA result in a change in amino acid sequence in proteins Evidence that a change in a single nucleotide of DNA can cause a genetic disorder Molecular organization of globin gene clusters shows how gene expression is regulated The Alpha-Globin Cluster Two copies of the alpha-globin gene, the zeta gene, and pseudogenes on chromosome 16 Pseudogenes Pseudogenes Nonfunctional genes that are closely related (by DNA sequence) to functional genes present elsewhere in the genome The Beta-Globin Cluster The beta-globin gene, four beta-like genes, and one pseudogene on chromosome 11 Globin Gene Expression Changes During Development Treating Hemoglobin Disorders Through Gene Switching Fetal hemoglobin has two alpha globins and two gamma globins Gamma globins, part of the beta cluster, are switched off at birth, and beta gene is activated Treatment with an anticancer drug, hydroxyurea, reactivates gamma genes Fetal hemoglobin reappears in red blood cells Two Categories of Genetic Disorders of Hemoglobin Hemoglobin variants Alpha and beta globins with variant amino acid sequences More than 400 hemoglobin variants identified Thalassemias An imbalance in production of globins, which affects transport of oxygen within the body Beta-Globin Polypeptide Variants Exploring Genetics:The First Molecular Disease Studies by Linus Pauling and James Neel concluded that a mutant gene involved in the synthesis of hemoglobin causes sickle cell anemia, and that a genetic disorder can be caused by a defect in a single molecule Keep In Mind Sickle cell anemia is caused by substitution of a single amino acid in beta globin Thalassemias: Another Inherited Hemoglobin Disorder Normally, equal amounts of alpha and beta globin are produced and hemoglobin consists of two alpha globin chains and two beta globin chains Thalassemias Disorders associated with an imbalance in the production of alpha or beta globin Causes the formation of hemoglobin molecules with an abnormal number of alpha or beta globins These hemoglobins do not bind oxygen efficiently and can be lethal Alpha and Beta Thalassemia Alpha thalassemia Genetic disorder associated with an imbalance in the ratio of alpha and beta globin caused by reduced or absent synthesis of alpha globin Usually caused by deletion of alpha globin genes Beta thalassemia Genetic disorder associated with an imbalance in the ratio of alpha and beta globin caused by reduced or absent synthesis of beta globin Usually caused by mutations in beta globin genes Genetic Differences in Ability to Taste Bitter taste perception prevents us from eating poisonous substances The TAS2R38 gene encodes a receptor for a bitter tasting compound called PTC About 70% of people can taste PTC and have the genotype TT or Tt About 30% of people are non-non-tasters and have the genotype tt 30% in U.S. whites 3% in U.S. blacks Genetic Differences in Ability to Smell Two-thirds of people tested could smell pink flowers but not red ones; the rest could smell red flowers but not pink ones Pharmacogenetics Pharmacogenetics A branch of genetics concerned with identifying inherited genetics polymorphisms that underlie differences in the response to drugs Variations in the amino acid sequences of proteins affect the way individuals react to prescription drugs and chemicals in the environment Each individual is biologically and biochemically unique Pharmacogenetics Individual differences in reactions to therapeutic drugs represent a "hidden" set of phenotypes that are not revealed until exposure occurs Understanding the genetic basis for these differences is the concern of pharmacogenetics and may lead to customized drug treatment for infections and other diseases Drug Sensitivities are Genetic Traits Tamoxifen is a pro-drug that is administered for estrogen receptor-positive breast cancer CYP2D6 metabolizes tamoxifen to endoxifen 7-10% of women with breast cancer have a variant allele of CYP2D6 ("poor metabolizer") Drug Sensitivities are Genetic Traits Antidepressants that inhibit the activity of CYP2D6 decrease the effectiveness of tamoxifen Ecogenetics Ecogenetics The study of genetic variation that affects responses to environmental chemicals Parathione - organophsphate insecticide that is toxic to human nervous system Paraoxonase gene has two alleles, Q and R R/R: more resistant Q/Q: highly sensitive Keep In Mind Small differences in proteins can have a large effect on our ability to taste, smell, and metabolize medicines and environmental chemicals

Enzymes and Metabolic Pathways Enzyme A protein that catalyzes chemical reactions in the body without being altered itself Substrate The specific compound acted on by an enzyme Product The specific compound that results from enzymatic action Metabolism

epigenetics and cancer

Epigenetic changes to DNA can alter gene expression and contribute to cancer Abnormal DNA methylation is associated with many types of cancers

Essential amino acids Amino acids that cannot be synthesized in the body and must be supplied in the diet Phenylalanine is an essential amino acid and the starting point for a network of metabolic reactions

Gene Expression andGene Regulation Chapter 9 Dr. Ed Michaud HSC 3240 The Link between Genes and Proteins At the beginning of the 20th century, Garrod proposed that genetic disorders such as alkaptonuria result from biochemical alterations An Inborn Error of Metabolism Alkaptonuria Affected individuals have urine that turns black when exposed to air Garrod discovered that the urine had large quantities of alkapton (homogentisic acid) Concluded that affected individuals cannot convert alkapton into other products, as normal people can Referred to this condition as an 'inborn error of metabolism' Suggested that this and other phenotypes may be caused by a biochemical abnormality linked to a mutation The Relationship Between Genes and Enzymes Using Neurospora, Beadle and Tatum showed that mutations can produce a loss of enzyme activity and a mutant phenotype Beadle proposed that genes control the synthesis of proteins and that protein function is responsible for producing the phenotype Keep In Mind The information necessary to make proteins is encoded in the nucleotide sequence of DNA The Genetic Code: The Key to Life Information transferred from DNA to mRNA is encoded in a set of three nucleotides (codons) Codons Triplets of nucleotides in mRNA that encode the information for a specific amino acid in a protein Of 64 possible codons, 61 code for the 20 amino acids found in proteins, and 3 are stop codons Codons, The Genetic Code Keep In Mind The three RNA nucleotides in a codon are a universal language specifying the same amino acid in almost all organisms Genetic Information Is Stored in DNA Genes are made of DNA, and proteins are the products of genes, therefore DNA must control protein production The phenotypes of cells, tissues, and organisms are the result of protein function In Watson and Crick's model, DNA stores genetic information in its nucleotide sequence Four DNA nucleotides must code for the 20 amino acids used to make proteins Tracing the Flow of Genetic Information from Nucleus to Cytoplasm Transfer of information from the linear sequence of nucleotides in DNA to the linear sequence of amino acids in a protein occurs in two steps: transcription and translation The Flow of Genetic Information Transcription (DNA to mRNA) Transfer of genetic information from the base sequence of DNA to the base sequence of RNA, mediated by RNA synthesis Translation (mRNA to protein) Conversion of information encoded in the nucleotide sequence of an mRNA molecule into the linear sequence of amino acids in a protein The Link Between Transcription and Translation Messenger RNA (mRNA) A single-stranded complementary copy of the DNA sequence in a gene The Flow of Genetic Information Organization of a Eukaryotic Gene Initiation and Termination of Transcription Promoter region A region of a DNA molecule to which RNA polymerase binds and initiates transcription Terminator Region The nucleotide sequence at the end of a gene that signals the end of transcription Processing and Splicing mRNA Introns DNA sequences present in some genes that are transcribed, but are removed during processing and therefore are not present in mature mRNA Exons DNA sequences that are transcribed, joined with other exons in mRNA processing, and translated into the amino acid sequence of a protein Transcription of DNA to mRNA In transcription, one of the DNA strands of a gene is used as a template for making a complementary strand of RNA, which is then processed into mRNA Transcription has three stages: initiation, elongation, and termination Transcription requires DNA, RNA polymerase, and nucleotides (Adenine, Uracil, Cytosine, Guanine) Transcription of a Gene Produces RNA Transcription of a Gene Produces RNA Pre-mRNA Transcription produces large mRNA precursor molecules called pre-mRNA Pre-mRNA is processed in the nucleus to produce mature mRNA Processing and Splicingpre-mRNA to mRNA Processing and Splicingpre-mRNA to mRNA Cap A modified base (guanine nucleotide) attached to the 5' end of eukaryotic mRNA molecules during RNA processing Poly-A tail A string of 30-100 adenine (A) nucleotides added to the 3'end of mRNA molecules during RNA processing Splicing The introns are spliced out to produce mature mRNA Alternative Splicing of pre-mRNA to mRNA Selective splicing of introns to produce many mature mRNA molecules from a single pre-mRNA sequence Allows for one gene to code for more than one protein Explains why more than 20,000 proteins can be produced from the 20,000 genes in the human genome Alternative Splicing of pre-mRNA to mRNA mRNA is Transported from Nucleus to Cytoplasm for Translation into Protein After processing and splicing, mRNA is transported from the nucleus to the cytoplasm where the encoded information is translated into the amino acid sequence of a protein Translation Requires the Interaction of Several Components Translation requires the interaction of mRNA, ribosomes (rRNA), tRNA molecules, amino acids enzymes, and energy sources Twenty different amino acids are the building blocks used to make proteins Interaction of Components Ribosomes are the workbenches on which protein synthesis occurs (composed of two subunits of rRNA combined with proteins) tRNA molecules are adapters that recognize amino acids and the nucleotide sequence in mRNA, the gene transcript Amino Acids Commonly Found in Proteins Amino Acid Structure Amino group A chemical group (NH2) found in all amino acids and at one end of a polypeptide chain Carboxyl group A chemical group (COOH) found in all amino acids and at one end of a polypeptide chain R group Each amino acid has a different side chain, called an R group An R group can be positively or negatively charged or neutral An Amino Acid Linking Amino Acids to Form Polypeptides Peptide bond A covalent chemical link between the carboxyl group of one amino acid and the amino group of another amino acid Polypeptide A molecule made of amino acids joined together by peptide bonds Polypeptides Have Two Different Ends N-terminus The end of a polypeptide or protein that has a free amino group (the first amino acid in the polypeptide) C-terminus The end of a polypeptide or protein that has a free carboxyl group (the last amino acid in the polypeptide) Ribosomes Ribosomes Cytoplasmic particles composed of two subunits that are the site of protein synthesis Ribosomal RNA (rRNA) RNA molecules that form part of the ribosome Ribosomes: Small and Large Subunits tRNA Transfer RNA (tRNA) A small RNA molecule that contains a binding site for a specific type of amino acid and has a three-base segment known as an anticodon that recognizes a specific base sequence in messenger RNA tRNA has been called an adaptor molecule because it recognizes both mRNA and an amino acid tRNA Anticodon A group of three nucleotides in a tRNA molecule that pairs with a complementary sequence (known as a codon) in an mRNA molecule Transfer RNA (tRNA) Translation of mRNA into Protein Translation of mRNA to protein occurs in the cytoplasm of the cell Translation proceeds through three stages: Initiation Elongation Termination Initiation: Ribosomes Bring mRNA and tRNA Together Initiation complex The initiator tRNA (which carries the amino acid, that methionine) is loaded onto the small ribosomal subunit The small subunit attaches to the 5' end of the mRNA and scans for the START codon (AUG) The anticodon of the tRNA binds to the start codon of the mRNA The large ribosomal subunit binds to the small ribosomal subunit Initiation is complete and elongation is ready to begin Initiation: Ribosomes Bring mRNA and tRNA Together Start codon A codon present in mRNA that signals the location for translation to begin The codon AUG functions as a start codon (which codes for the amino acid, methionine) Elongation: Forming a Polypeptide Elongation The ribosome moves along the mRNA Within the ribosome, tRNA anticodons bind to complementary codons in the mRNA, linking amino acids and producing a growing polypeptide chain Termination Stop codon A codon present in mRNA that signals the end of a growing polypeptide chain The codons UAG, UGA, and UAA function as stop codons Stop codons do not code for amino acids and there are no tRNAs for the stop codons At termination, the polypeptide is released from the ribosome and undergoes a conformational change to produce a functional protein Translation Translation Exploring Genetics: Antibiotics and Protein Synthesis Antibiotics are produced by microorganisms as a defense mechanism Many antibiotics affect one or more stages in protein synthesis Tetracycline: initiation of translation Streptomycin: codon-anticodon interaction Erythromycin: ribosome movement along mRNA Keep In Mind Genetic information for proteins, in the form of mRNA, moves from the nucleus to the cytoplasm, where it is translated into the amino acid sequence of a polypeptide Polypeptides Fold into Three- Dimensional Shapes to Form Proteins After synthesis, polypeptides fold into a three-dimensional shape, often assisted by other proteins, called chaperones Mutations in chaperones can cause genetic disorders Post-Translational Modification Polypeptides can be chemically modified in many different ways, producing functionally different proteins from one polypeptide attaching lipids to the polypeptides attaching sugars to the polypeptides chemically changing some amino acids removal of some amino acids After a polypeptide has been folded, modified, and becomes functional, it is called a protein Protein Processing, Sorting, and Transport After polypeptides leave the ribosome, they are folded, modified, and transported Polypeptides made on cytoplasmic ribosomes are folded and remain in the cell Polypeptides made on ribosomes on the outer surface of the rough ER enter the ER, where they are folded and chemically modified, and transported to the Golgi complex for packaging and secretion Protein Processing, Sorting, and Transport Effects of Protein Processing Humans have 20,000 to 25,000 protein-coding genes, but can make over 100,000 different proteins Alternative transcription start sites (multiple AUGs) Alternative splicing of mRNA processing Proteome The set of proteins present in a particular cell at a specific time under a particular set of environmental conditions Keep In Mind Once polypeptides fold into a three-dimensional shape, are chemically modified, and become functional, they are called proteins Mutations that prevent proper folding or cause misfolding can be the basis of disease Protein Structure and Function Are Related The structure and function of a protein are determined by the specific sequence of its amino acids Four levels of protein structure are recognized, three of which result from the primary sequence of amino acids in the backbone of the protein chain Four Levels of Protein Structure Primary structure The amino acid sequence in a polypeptide chain Secondary structure The pleated or helical structure in a protein molecule that is brought about by the formation of bonds between amino acids Four Levels of Protein Structure Tertiary structure The three-dimensional structure of a protein molecule brought about by folding of helical or pleated sheet regions back onto themselves Quaternary structure Some proteins are composed of more than one polypeptide chain The structure formed by the interaction of two or more polypeptide chains in a protein Levels of Protein Structure Protein Folding: A Factor in Disease Defective folding prevents the formation of a functional protein, producing a mutant phenotype Some proteins can refold, changing their three-dimensional structure and causing disease Protein refolding diseases are called prion diseases Protein-Folding Diseases Prion A protein folded into an infectious conformation that is the cause of several disorders, including Creutzfeldt-Jakob disease and mad cow disease Mad-cow disease A prion disease of cattle, also known as bovine spongiform encephalopathy, or BSE Prions Several Mechanisms Regulate the Expression of Genes Chromatin Remodeling DNA Methylation and Gene Expression RNA Interference Translational and Post-translational Regulation

beadle and tatum

received nobel prize in 1958 or their work with bread mold - for revealing the pathway from genes to proteins to phenotypes.

65% of CF patients have this delta 508 mutation

results in a completely non functional protein. have a severe form of the disease.

Remember

Genes are made of DNA, and proteins are the products of genes, therefore DNA must control protein production The phenotypes of cells, tissues, and organisms are the result of protein function In Watson and Crick's model, DNA stores genetic information in its nucleotide sequence Four DNA nucleotides must code for the 20 amino acids used to make proteins

caretaker genes

Genes that help maintain the integrity of the genome; for example, DNA repair genes MSH2 and MLH1 are examples

gatekeeper genes

Genes that regulate cell growth and passage through the cell cycle; for example, tumor suppressor genes and many proto-oncogenes APC is an example

Genome Alterations: Mutation and Epigenetics Chapter 11 Dr. Ed Michaud HSC 3240 Mutations in DNA Mutations are changes in the normal nucleotide sequence of DNA Mutations can occur: spontaneously as a result of errors in DNA replication, or they can be induced by exposure to radiation or chemicals Two Categories of Mutations Somatic Mutations Occur in cells of the body that do not form gametes Are not transmitted to future generations Germ-line Mutations Occur in cells that produce gametes Transmitted to future generations-inherited Mutations Can Be Detectedin Several Ways Mutations can be classified in a variety of ways by using criteria such as: Pattern of inheritance Phenotype Biochemistry Degrees of lethality Mutations in germ cells are heritable, but mutations in somatic cells are not heritable Identifying the Source of a New Mutation The origins of autosomal dominant mutations are easiest to detect because they are expressed in the heterozygous condition Sudden appearance of a dominant mutation in a family can be observed in a single generation Accurate pedigree information can be used to identify the individual in whom a mutation arose Pedigree: An Autosomal Dominant Trait Recessive Mutations It is more difficult, but it may also be possible to identify the origin of an X-linked recessive mutation May be detected by examining males in a family line If the mutation is autosomal recessive, it is almost impossible to identify the original mutant individual Because the phenotype is only present in people who are homozygous for the mutation Pedigree: An X-Linked Recessive Trait Queen Victoria and hemophilia Measuring Spontaneous Mutation Rates Mutation rate The number of mutated alleles per locus per generation Studies of mutation rates in a variety of dominant and X-linked recessive traits indicate: mutations in the human genome are rare events; about 1 x 10-6 alleles per locus per generation (1 allele out of 1 million for each gene will have a mutation each generation); but mutation rates vary widely for different genes Mutation Rates for Specific Genes Can Sometimes be Measured Mutation rates can be measured only for dominant alleles under certain conditions Phenotype must never be produced by recessive alleles Phenotype must always be fully expressed and completely penetrant Paternity must be clearly established Phenotype must never be produced by non-genetic agents Phenotype must be produced by mutation of only a single gene Mutation Rates and Dominant Mutations Widely varying mutation rates have been calculated for dominant traits such as neurofibromatosis, Huntington disease, and achondroplasia (a form of dwarfism) Mutation Rates for Selected Genes Why Do Genes Have Different Mutation Rates? Several factors influence mutation rate Size of the gene: Larger genes have higher mutation rates Nucleotide sequence: Presence of nucleotide repeats (such as CGG or CAG) are associated with higher mutation rates Spontaneous chemical changes: G/C base pairs are more likely to mutate than A/T pairs Environmental Factors Influence Mutation Rates Mutations can result from: errors in normal cellular functions, such as in the replication of DNA the action of agents that attack DNA, which can originate from inside or outside of our bodies, and include chemicals and radiation Radiation Radiation Energy that is radiated or transmitted in the form of waves or moving subatomic particles Two main types of radiation Electromagnetic radiation - waves of energy Corpuscular radiation - moving subatomic particles Ionizing Radiation Can Cause Mutations Ionizing radiation Radiation that produces ions during interaction with other matter, including molecules in cells Can generate free radicals by splitting water molecules in cells into hydrogen ions (H+) and hydroxyl radicals (.OH) that can cause mutations in DNA If mutations are not repaired, cell death or cancer may occur Background Radiation Background radiation Natural sources of radiation in the environment that contributes to radiation exposure Sources include our own bodies, the food we eat, the air we breathe, and the bricks in our houses How Much Radiation Are We Exposed To? Rem (radiation equivalent in man) Unit of radiation exposure used to measure radiation damage in humans The amount of ionizing radiation that has the same effect as a standard amount of x-rays Millirem (mrem) 1,000 millirems is equal to 1 rem U.S. Sources of Radiation Exposure In the U.S., the average person is exposed to about 360 mrem/year 81% of which is from natural background sources A dose of 5,000 mrem can: Cause somatic mutations Increase susceptibility to cancer Chemicals Can Cause Mutations Some chemicals cause nucleotide substitutions or change the number of nucleotides in DNA Other chemicals structurally change the bases in DNA, causing a base pair change after replication Chemicals that cause mutations are called mutagens Base Analogs Base analogs Mutagenic chemicals that structurally resemble nucleotides and are incorporated into DNA or RNA during synthesis Example: 5'-bromouracil replaces thymine Results in a T/A → C/G substitution mutation Thymine and 5'-Bromouracil Chemical Modifications of Bases Some chemical mutagens directly modify the structure of one of the bases in DNA, changing it to another base Example: Nitrous acid (HNO2) changes cytosine into uracil, resulting in a G/C → A/T mutation Conversion of Cytosine to Uracil Chemicals That Bind to DNA Chemicals that bind directly to DNA (intercalating agents) distort the double helix, resulting in the addition or deletion of a base pair during DNA replication, causing a frameshift mutation Example: Acridine orange replaces a base pair Acridine Orange Produces frameshift mutations Mutations at the Molecular Level: DNA as a Target Mutations arise spontaneously as the result of errors in DNA replication or as the result of exposure to radiation and chemicals At the molecular level, mutations can involve substitutions, insertions, or deletions of one or more nucleotides in DNA Two Types of Mutations Nucleotide substitutions Mutations that involve substitution of one or more nucleotides in a DNA molecule with other nucleotides (changes the sequence of the DNA but not the number of nucleotides) Frameshift mutations Mutational events in which a number of bases (other than multiples of three) are inserted into or deleted from DNA, causing a shift in the codon reading frame Many Hemoglobin Mutations are Caused by Nucleotide Substitutions Hemoglobin variants provide many examples of how a change in one nucleotide in a gene can affect protein structure and function Three types of nucleotide substitutions Missense mutations Sense mutations Nonsense mutations Missense Mutations Missense mutations Mutations that cause the substitution of one amino acid for another in a protein Example: As the result of different DNA mutations in the beta-globin gene, a GAG codon in the mRNA can be changed to GUG, AAG, or GCG Hemoglobin Variants: Single Nucleotide Substitutions Sense Mutations Sense mutations Mutations in a single nucleotide can change a termination codon into one that codes for an amino acid, producing longer-than-normal proteins Example: Stop codon UAA in alpha globin can mutate to CAA (Constant Springs-1) Alpha Globins with Extended Chains Nonsense Mutations Nonsense mutations Mutations that change a codon specifying an amino acid to one of three termination codons, producing a shorter-than-normal protein Example: A UAU codon in beta globin can mutate to a stop codon UAA Genetic Code Nucleotide Deletions and Insertions Cause Frameshift Mutations THE FAT CAT ATE HIS HAT Normal code THE FAA TCA TAT EHI SHA T Insertion of A causes a frameshift THE FTC ATA TEH ISH AT Deletion of A causes a frameshift Insertions Insertions change the reading frame, changing the amino acids in the protein Trinucleotide Repeats and Gene Expansions Trinucleotide repeats A mutation associated with the expansion in copy number of a nucleotide triplet in or near a gene Allelic expansion Increase in gene size caused by an increase in the number of trinucleotide sequences Potential for expansion is a characteristic of a specific allele Causes several different genetic disorders Mutations With Expanded Nucleotide Repeats Fragile-X Syndrome: The FMR1 Gene Alleles of the FMR1 gene contain CGG repeats Normal alleles: 5 to 52 repeats Premutation alleles: 60 to 200 repeats Fully mutant alleles: More than 230 repeats Sex of transmitting parent influences expansion Maternal transmission: Repeats expand Paternal transmission: Repeats remain constant or decrease Allelic Expansion in the FMR1 Gene Trinucleotide Repeat Expansion is Related to Anticipation Anticipation Onset of a genetic disorder at earlier ages and with increasing severity in successive generations Caused by increase in the number of trinucleotide repeats from one generation to the next Explains why disorders caused by trinucleotide repeats do not show simple Mendelian inheritance Anticipation: Myotonic Dystrophy Alleles of DMPK gene contain CTG repeats Normal: 5-34 repeats Premutation: 35-49 repeats Mutation: 50 or more repeats Repeats usually expand by maternal transmission (can be paternal) Keep In Mind Mutations in DNA can occur in several ways, including nucleotide substitution, deletion, insertion, and expansion of trinucleotide repeats Mutations and DNA DamageCan Be Repaired Not all mutations result in a permanent genetic change Cells have enzyme systems that repair DNA Correct errors in replication Repair damage caused by environmental agents such as ultraviolet light, radiation, and chemicals Rates of DNA Damage Maximum DNA Repair Rates DNA Polymerase DNA polymerase corrects mistakes in DNA replication (proofreading function) DNA Damage From UV Light Thymine dimer Chemical bonds formed between a pair of adjacent thymine bases in a DNA molecule Distorts the DNA molecule and affects replication Genetic Disorders Can Affect DNA Repair Systems Xeroderma pigmentosum autosomal recessive caused by mutations in genes that repair DNA skin cancer from sun exposure at a rate 1000 times greater than normal Keep In Mind Damage to DNA can be repaired during DNA synthesis and by enzymes that repair damage to DNA caused by radiation or chemicals Mutations, Genotypes, and Phenotypes In most genes associated with a genetic disorder, many different types of mutations can cause a mutant phenotype In the cystic fibrosis gene, more than 1900 different mutations have been identified, including deletions, nucleotide substitutions, and frameshift mutations Mutations in the Cystic Fibrosis Gene The Type and Location of a Mutation Within a Gene Are Important The wide range of mutations in genetic disorders leads to wide variation in clinical symptoms Depending on the mutation, symptoms can range from very mild to very severe More than 1,900 different mutations have been discovered in the CFTR gene Some people carry two different mutations (compound heterozygotes) Some Mutations in the CFTR Gene Epigenetics Epigenetics - Chemical modifications of DNA and its associated proteins that: Alter gene expression Without changing the nucleotide sequence of the DNA DNA Methylation - The addition of a methyl group to a DNA base (epigenetic modification) Occurs almost exclusively on cytosine bases adjacent to a guanine base (a CpG sequence) Methylation of cytosine bases in the promoter of a gene prevents it from being expressed Genomic Imprinting Is a Reversible Alteration of the Genome Genomic imprinting A difference in gene expression caused by DNA methylation that identifies a gene as coming from the mother or from the father Affects the expression of a gene, not the gene itself Takes place during gamete formation or early embryonic development It is an epigenetic modification that is reversible; it can change from generation to generation depending on whether it is being passed through the mother or through the father Evidence For Imprinting in Mammals Genomic Imprinting and Genetic Disorders Only segments of chromosomes 4, 8, 11, 15, 17, 18, and 22 are imprinted Only a small percentage of all genes are imprinted A small deletion in the long arm of chromosome 15 accounts for 80% of all cases of PWS and AS Prader-Willi syndrome (PWS): deletion inherited from father; deletion of a gene only expressed from the paternal chromosome (maternally imprinted) Angelman syndrome (AS): deletion inherited from mother; deletion of a different gene only expressed from the maternal chromosome (paternally imprinted) Genomic Imprinting and Genetic Disorders Uniparental disomy (UPD) A condition in which both copies of a chromosome are inherited from one parent About 20% of PWS and AS cases have no deletions, but UPD has been identified PWS: Both copies come from the mother (normal with no deletion) AS: Both copies come from the father (normal with no deletion) Genomic Imprinting is Not Permanent In each generation, the previous imprinting is erased and the gene is re-imprinted During gamete formation or early development Imprinting is an epigenetic change Involving reversible changes by chemical modifications to DNA and gene function without affecting the nucleotide sequence Imprinting Changes With Each Generation

benign

Harmless - does not invade other tissues

gene

sequence of DNA in the genome that is required for making a functional product. The functional products made by most genes are proteins. However, some genes code for functional RNA molecules, which do not code for proteins.

majority of colon cancers is

spontaneous

Angelman syndrome

If the same Microdeletion on Chrom15 that causes Prader Willi originates from the mother, the resulting disease is - from the mother.

gleevec

Imatinib - specifically designed to bind to a mutant protein so that it cannot phosphorylate. Gleevec inactivates the BCR-ABL protein; cancer cell stops dividing

translocations and hybrid gnes leading to leukemia

In CML, the C-ABL gene (chromosome 9) is connected to the BCR gene (chromosome 22) The hybrid gene encodes an abnormal protein that signals CML cells to divide

Transcription of DNA to mRNA

In transcription, one of the DNA strands of a gene is used as a template for making a complementary strand of RNA, which is then processed into mRNA Transcription has three stages: initiation, elongation, and termination Transcription requires DNA, RNA polymerase, and nucleotides (Adenine, Uracil, Cytosine, Guanine)

an inborn error of metabolism

Inborn error of metabolism The concept advanced by Sir Archibald Garrod that many genetic traits result from alterations in biochemical pathways Garrod's work suggested that heredity and metabolism are related

Familial retinoblastoma (hereditary)

Individuals inherit one mutant copy of RB1 gene and one normal copy of the RB1 gene Normal copy of RB1 gene acquires a spontaneous mutation 85% to 95% chance of developing the disease Usually involves both eyes and occurs earlier in life

Sporadic retinoblastoma

Mutations of both copies of RB1 gene occur in a single cell Usually involves one eye and occurs later in life

translocations

Many proto-oncogenes are located at or close to the breakpoints of chromosomal translocations involved with specific forms of leukemia

Metabolism The sum of all biochemical reactions by which cells convert and utilize energy

A PKU diet must contain phenylalanine levels high enough for normal development, but low enough to prevent mental retardation Screening Newborns for PKU Exploring Genetics: Dietary Management and Metabolic Disorders For PKU, a formula is prepared from enzymatically digested proteins (or synthetic mixtures of amino acids), fats, carbohydrates, and vitamin and mineral supplements A typical lunch might include vegetable soup, crackers, fruit cocktail, and formula What Happens When Women With PKU Have Children? A pregnant woman with PKU who eats a normal diet has high levels of phenylalanine in her blood

Monosaccharides and Disaccharides Metabolic Pathway of Lactose and Galactose Galactosemia is Caused by Enzyme Deficiency Galactosemia A heritable trait associated with the inability to metabolize the sugar galactose If left untreated, high levels of galactose-1-phosphate accumulate, causing hepatomegaly, cataracts and mental retardation Dietary treatment does not prevent long-term complications

xeroderma pigmentosum

Mutated single strand nucleotide excision repair gene, which prevents repair of thymidine dimers.; Dry skin w/ melanoma and other cancers ("children of the night"). UV radiation puts us at increased risk - XP patients are 1000 times greater - autosomal resessive casing damage in dna repair genes

Metabolism The sum of all biochemical reactions by which cells convert and utilize energy A Metabolic Reaction Enzyme, substrates, and product Enzymes and Metabolic Pathways Biochemical reactions in the cell are linked together to form metabolic pathways A chemical compound can be the product of one enzymatic reaction and the substrate for the next reaction in a metabolic pathway

Mutations that block one reaction in a pathway can produce mutant phenotypes in several ways Reactions in a Metabolic Pathway Genetic Disorders and Metabolism Are Related Inborn error of metabolism The concept advanced by Sir Archibald Garrod that many genetic traits result from alterations in biochemical pathways Garrod's work suggested that heredity and metabolism are related An Inborn Error of Metabolism Alkaptonuria An autosomal recessive trait with altered metabolism of homogentisic acid Affected individuals do not produce the enzyme needed to metabolize this acid, and their urine turns black Alkaptonuria: Metabolic Pathways of Phenylalanine Pedigree of Family with Alkaptonuria Phenylketonuria (PKU): A Mutation That Affects an Enzyme

Other forms of cancer are also associated with specific chromosomal abnormalities

Myeloblastic leukemia, Burkitt's lymphoma, multiple myeloma

Polypeptides Have Two Different Ends

N-terminus The end of a polypeptide or protein that has a free amino group (the first amino acid in the polypeptide) C-terminus The end of a polypeptide or protein that has a free carboxyl group (the last amino acid in the polypeptide)

Essential amino acids Amino acids that cannot be synthesized in the body and must be supplied in the diet Phenylalanine is an essential amino acid and the starting point for a network of metabolic reactions Phenylalanine Metabolism and PKU A mutation in a gene encoding the enzyme (PAH, phenylalanine hydroxylase) that controls the first step in the breakdown of phenylalanine causes phenylketonuria (PKU)

PKU Phenylketonuria (PKU) An autosomal recessive disorder of amino acid metabolism Results in light colored hair and skin, "musty" body odor, jerky arm and leg movements, and mental retardation if untreated The phenotype is caused by the buildup of phenylalanine and the products of secondary reactions PKU and Other Disorders of the Metabolic Pathways of Phenylalanine PKU Can Be Treated With Diet Infants with PKU can develop normally before birth, then develop neurological damage when fed a diet containing protein

keep in mind

Phenotypes are the "visible" end product of a chain of events that starts with the gene, the mRNA, and the protein product

Phenylalanine Metabolism and PKUV A mutation in a gene encoding the enzyme (PAH, phenylalanine hydroxylase) that controls the first step in the breakdown of phenylalanine causes phenylketonuria (PKU)

Phenylalanine Metabolism and PKU A mutation in a gene encoding the enzyme (PAH, phenylalanine hydroxylase) that controls the first step in the breakdown of phenylalanine causes phenylketonuria (PKU)

initiation

RNA polymerase and several

Interaction of Components

Ribosomes are the workbenches on which protein synthesis occurs (composed of two subunits of rRNA combined with proteins) tRNA molecules are adapters that recognize amino acids and the nucleotide sequence in mRNA, the gene transcript

alternative/selective splicing of pre MRNA results in

Selective splicing of introns to produce many mature mRNA molecules from a single pre-mRNA sequence. Allows for one gene to code for more than one protein Explains why more than 20,000 proteins can be produced from the 20,000 genes in the human genome

Chromosome rearrangements can be related to cancer

Some cancers, such as chronic myelogenous leukemia (CML), are caused by translocation events, creating hybrid genes that activate cell division Philadelphia chromosome

What happens to a polypeptide when it is released from the ribosome?

Some polypeptides enter the ER, where they are folded and modified. b. Polypeptides made on cytoplasmic ribosomes are folded and remain in the cell. d. Polypeptides folded in the ER are transported to the Golgi complex to be packaged for secretion.

metastisize

Spread When the defective cells spread to other parts of the body

The ________ of the tRNA molecule pairs with ________ molecule.

The anticodon of the tRNA molecule pairs with a complementary codon in the mRNA molecule

keep in mind

The information necessary to make proteins is encoded in the nucleotide sequence of DNA

proteome

The set of proteins found in a specific cell under a given set of conditions.

keep in mind

The three RNA nucleotides in a codon are a universal language specifying the same amino acid in almost all organisms

amino acids are

subunits of proteins

ATAXIA TELANGIECTASIA

This condition is due to a mutation in the ATM gene which inhibits the rocovery of the cell to double-strand DNA breaks such as those caused by X-rays. Present w/ numerous oculocutaneous skin lesions, progressive cerebellar ataxia, relative immunodeficiency, and are particularly susceptible to lymphomas & leukemias.

premessenger RNA

Transcription produces large mRNA precursor molecules called pre-mRNA Pre-mRNA is processed in the nucleus to produce mature mRNA

transcription

Transfer of genetic information from the base sequence of DNA to the base sequence of RNA, mediated by RNA synthesis

codon

Triplets of nucleotides in mRNA that encode the information for a specific amino acid in a protein Of 64 possible codons, 61 code for the 20 amino acids found in proteins, and 3 are stop codons A codon is a series of three RNA nucleotides

genomic imprinting

Variation in phenotype depending on whether an allele is inherited from the male or female parent. a phenomenon in which expression of an allele in offspring depends on whether the allele is inherited from the male or female parent Certain traits whose expression varies, depending on the parent from which they are inherited; diseases that result from imprinting are Prader-Willi and Angelman syndromes

P53 gene

What tumor suppressor gene prevents a cell with damaged DNA from entering the S phase?

embryo splitting

When an early embryo is split up into separate cells, each of which is allowed to grow into a new embryo.

Archibald Garrod

Who first suggested that genes dictate phenotypes through enzymes that catalyze specific chemical reactions?

DNA methylation

the addition of a methyl group to a DNA base (epigenetic modification) occurs almost exclsively on cytosine bases adjacent yo a quanine base. (a CpG sequence)

uniparental disomy

a condition in which both copies of a chromosome are inhereted form one parent.

clone

a group of genetically identical cells or organisms derived from a single cell or individual by some kind of asexual reproduction - two things that came from the same ancestor they are genetically identical.

Translation requires

the interaction of mRNA, ribosomes (rRNA), tRNA molecules, amino acids enzymes, and energy sources Twenty different amino acids are the building blocks used to make proteins

neoplasia

the new and abnormal development of cells that may be benign or malignant - the process of developing cancer

the primary risk facto rfor cancer is

age

Ribosomes are ________.

b. cytoplasmic organelles with two subunits c. composed of rRNA and proteins d. the site of protein synthesis

CABL on all the time would be bad

because lots of things would be phosphoralized

sporadic cancer

cancer that originates from the accumulation of mutations

mutations in mcrosatellites

cause muttion in neighboring genes

malignant

causing harm - capable of spreading - must meastisize

nuclear transfer

cell fusion

epigenetics

chemical modifications of DNA and its associated proteins that alter gene expression, without changing the nucleotide sequence of the DNA.

alkaptonuria

disorder in which a newborns urine will turn black when exposed to air caused by nonconversion of homogentisic acid - discovered by garrod

deletion from mom

imprinted from dad

deletion from dad

imprinted from mom

cancer is a genetic disease but all cancer is not

inherited

when you mutate RB

it cant be active, that regulatory is gone, and cancer cells can bypass that check point

FAP 85%

lynch syndrome 15% - most common form of inherited colorectal cancer and endometreal cancer.

cancer can be affected by

environmental and behavioral factors

FAP

familial adenomatous polyposis - hundreds of colon polyps that always become cancer as starts as early as 8 - 9 years old

Patients with Lynch syndrome are also at increased risk

for cancers of the ovary, stomach, small intestine, pancreas, upper urinary tract, hepatobiliary tract, brain, skin, and prostate

Tumor supressor genes

genes encoding protein that supress cell division

1st step

getting a mutant APC gene from one of your parents

polyps are

growth attached to the substrate by small stalks

he structure and function of a human protein are determined by ________.

the specific sequence of its amino acids.

The 20 amino acids commonly found in proteins differ from each other in ________.

their R groups

In translation, the initiation complex is composed of ________.

trna - a small ribosomal subunit - mRNA

retinoblastoma

tumor arising from a developing retinal cell - Retina - layer of nerve tissue in back of eye that is sensitive to light A malignant tumor of the eye arising in retinoblasts Because mature retinal cells do not transform into tumors, this tumor usually occurs only in children Usually diagnosed between 1 to 3 years of age Caused by mutations in the RB1 gene on chromosome 13

two characteristics of cancer

uncontrolled cell division dividing like crazy or no apoptosis the ability to metastasize

pRB

what protein is a master brake of the cell cycle - do not go through that g1 to s checkpoint

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