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BIOL 4003 Week 13 Notes

by: Rachel Heuer

BIOL 4003 Week 13 Notes 4003

Marketplace > University of Minnesota > Biology > 4003 > BIOL 4003 Week 13 Notes
Rachel Heuer
U of M
GPA 3.87

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These notes cover week 13 lectures.
Principles of Genetics
Robert Brooker
Class Notes
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This 9 page Class Notes was uploaded by Rachel Heuer on Tuesday April 19, 2016. The Class Notes belongs to 4003 at University of Minnesota taught by Robert Brooker in Spring 2016. Since its upload, it has received 8 views. For similar materials see Principles of Genetics in Biology at University of Minnesota.


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Date Created: 04/19/16
Chapter 23: -   Functional genomics: Aims to figure out the roles of genetic sequences in species o   Aims to understand gene function o   Proteome: Entire collection of proteins that an organism can make o   Proteomics: Work towards understanding functional roles of proteins in species §   Aims to understand the interplay among proteins o   Bioinformatics: Uses computational/mathematical approach to analyze biological information §   Often thought of in terms of extracting information from genetic data -   Microarray can identify genes that are transcribed o   Can analyze 1000s of genes at a time o   DNA microarray is a small silica or glass slide that is dotted with many sequences of DNA §   Each sequence is complementary to known gene §   Fragments are made synthetically §   These sequences of DNA will act as probes to identify genes that have been transcribed o   Steps §   First isolate mRNA from cell §   add reverse transcriptase with fluorescently labeled dNTPs §   Overlay microarray with fluorescent cDNAs §   Wash off excess cDNAs that haven’t yet bound §   Placed in laser scanner to see fluorescent spots §   Are used to analyze gene regulation and expression -   Chromatin Immunoprecipitation (ChIP): determines if proteins can bind to specific regions of DNA in chromatin of living cells o   Proteins in living cells are crosslinked to DNA with formaldehyde (in cell) o   Cells are lysed and DNA is broken into small pieces o   Antibody is used to precipitate the protein of interest o   DNA is chemically freed from the cross-links o   DNA amplified via PCR o   Sequenced of DNA is identified directly or by using it as a probe on a microarray §   Fluorescent spots on microarray tell us where in the genome the protein binds -   Gene knockout collections o   Goal is to determine function of every gene in a species genome o   Can get large number of one organism and just knockout one gene in each §   The phenotype could indicate function §   Could combine knockouts to study pathways o   Can knockout via transposable elements and homologous recombination o   Can’t determine protein function if the knockout is lethal -   Bioinformatics o   Using a computer to analyze genetic sequences o   3 components §   Computer §   Computer program •   Defined series of operations that can analyze data in desired manner §   Data o   First step is generating a computer data file (suitable for analysis) §   Collection of information in a form suitable for storage and manipulation by a computer o   For program aimed at translating §   DNA sequence input §   Tell computer to translate §   Computer reads all three reading frames (actually six, 3 forward and 3 back) and outputs whichever one the reader wants •   Wrong reading frames are short because they experience a stop codon prematurely •   Longest reading frame is usually the correct one o   Much faster than a human can work and completely accurate o   Useful when user does not know where start codon is §   Or which direction the coding sequence goes o   Amount of genetic information stored in research databases is enormous §   Large numbers of computer data files are collected and stored in a single location, a database •   Files are typically annotated with gene sequence, name of gene, description of gene and significance of gene o   Different computational Strategies §   Computer programs can be designed to locate to locate meaningful features within very long sequences §   Imagine 54 random English letters •   One program could locate all the English words within the sequence •   Another could locate a series of words that make up a grammatically logical sentence •   Another can locate patterns of letters that occur in both the forward and reverse directions §   Sequence Recognition: Program has information that specific sequence of symbols has special meaning •   First program (info = dictionary to make words) •   Second program (sequence organization) §   Pattern recognition: Does not rely on specialized sequence information rd •   Look for patterns of symbols (3 program) o   Identification of structural genes §   Locate specialized sequences (sequence elements) within a very long sequence •   Search by signal: program looks for known sequence elements that are normally found in genes o   Promoter, start/stop codons •   Search by content o   Identifies sequences that differ significantly from a random distribution o   Codon bias §   Locate an organization of sequences or sequence elements •   2 program §   Locate a pattern of sequences •   3 program §   Can locate coding regions by searching for translational reading frame •   ORF (open reading frame) is a nucleotide sequence that does not contain any stop codons •   In prokaryotes, long ORFs typically means gene sequences •   Doesn’t work as well in eukaryotes to find ORFs because of the presence of introns •   Computer program can translate genomic DNA sequences into all three frames and look for the longest ORF o   It is also possible that a reading frame could proceed from right to left o   Programs can identify homologous sequences §   DNA sequencing allows geneticists to examine evolutionary relationships at molecular level §   Homologous means derived from same ancestral gene •   Very similar sequences!!!! •   Have accumulated some mutations over time that have made them slightly different §   When two homologous genes are found in different species they are orthologs §   Paralogs: two or more copies of homologous gene within the same organism •   A gene family consists of two or more copies of homologous genes within the genome of a single organism §   Homologous does not mean similar •   Homology implies a common ancestry •   Similarity means sequence similarity •   In many cases, similarity is due to homology, but this is not always the case §   Homology is useful because it helps determine the function of proteins in other organisms •   Homology between genetic sequences can be identified by computer programs and databases •   BLAST (basic local alignment search tool) compares your sequence to other sequences in organisms o   Starts with genetic sequence and locates homologous sequences in large database §   Homology in protein sequence is easier to find than DNA sequence homology o   Can show how similar a protein is in different organisms §   Can then determine function of proteins easily o   Blast search output is based on E-value §   Represents likelihood match is due to random chance §   Small E-value means it is unlikely similarity is due to random events (genes are likely homologous) o   The order of matches follows the evolutionary relatedness of the various species Chapter 24: -   Thousands of genes cause diseases in humans o   Many occur due to mutations in a single gene §   Also can be caused be mutations in multiple genes •   Multifactorial -   Observations of human diseases o   Geneticists want to know the relative contributions from genetics and environment o   Geneticists cannot conduct crosses o   Must rely on analyses of families that already exist through pedigrees -   Rules (Many genetic diseases correlate with multiple of these): o   When individual exhibits disease, it is more likely to occur in blood relatives than general population o   Identical twins share same disease more often than fraternal twins §   Identical twins are also called monozygotic twins (formed from the same sperm and egg) §   Fraternal twins are also called dizygotic twins (formed from separate pairs of sperm and egg) §   Concordance: Degree to which a disease is inherited •   Refers to percentage of twin pairs in which both twins would show the disorder/trait •   Theoretical value is higher than actual value o   Genetic disease does not spread to individuals sharing similar environmental conditions o   Different populations have different frequencies of disease o   Disease develops at characteristic age §   Age of onset o   Human disease may resemble a genetic disorder that is already known to have a genetic basis in an animal o   Correlation is shown between a disease and a mutant human gene or a chromosomal alteration -   Pedigree analysis: Pattern of inheritance of monogenic disorders can be deduced by looking at pedigrees o   Must obtain data from large pedigrees with many affected individuals -   Tay-sachs disease: individuals appear healthy at birth but develop neurodegenerative symptoms at 4-6 months (AOO) o   Symptoms = cerebral degeneration, blindness and loss of motor function o   Die at 3 or 4 years of age o   More frequent in Jews o   Is the result of a mutation in a gene that encodes the enzyme hexosaminidase A (hexA) §   Breaks down lipids §   If hexA is not active, accumulation of lipids occurs in the cells of the CNS, which causes the neurodegenerative symptoms o   Inherited in an autosomal recessive manner §   Four features of autosomal recessive inheritance •   Affected offspring can have 2 unaffected parents •   When two unaffected heterozygotes have children, 25% will be affected on average •   Two affected individuals will have 100% affected offspring •   Occurs in same frequency in both sexes §   Disorders that involve defective enzymes/proteins typically have autosomal recessive inheritance mode of transmission •   Heterozygote carrier has 50% of the normal enzyme o   This is sufficient for a normal phenotype •   Common way of inheritance -   Huntingtons Disease: Degeneration of neurons in the brain o   Personality changes, dementia, and early death o   Is the result of a mutation in a gene that encodes a protein termed huntingtin §   Causes an aggregation of protein in neurons o   Autosomal dominant inheritance o   Five common features: §   Every affected individual has at least one affected parent •   Can be altered by reduced penetrance §   Affected individual with 1 affected parents will produce 50% affected offspring §   2 affected heterozygotes à 25% unaffected offspring •   75% affected §   occurs with the same frequency in both sexes §   Homozygote is more severely affected (often is lethal) compared to the heterozygote §   Common explanations for dominant disorders: •   Haploinsufficiency: o   heterozygote has 50% of normal protein o   this is not enough for the normal phenotype •   Gain of function mutations: o   Mutation changes protein so it gains a new function •   Dominant-negative mutation: o   Change of gene product acts antagonistically to the normal product §   Autosomal dominant diseases are not as common as autosomal recessive, but are not rare -   X-linked recessive inheritance o   Problem more so for males §   Only have one copy of the x chromosome (hemizygous) o   Female heterozygote will pass trait to half her sons o   3 common features of X-linked recessive inheritance: §   Males are more likely to exhibit the trait §   Mothers of affected males often have brothers/fathers who are affected with the same trait §   Daughters of affected males will produce 50% affected sons -   X-linked dominant inheritance is rare o   Characteristics of such disorders: §   Males are often more severely affected •   Females may be less affected due to wild-type copy on second X §   Females are more likely to exhibit the trait when it is lethal to males §   Affected females have a 50% chance of passing the trait to daughters o   Often caused by a new mutation -   Genetic disorders often exhibit locus heterogeneity o   Locus heterogeneity: refers to the phenomenon that a disease can be caused by mutations in two or more different genes -   Cancer: caused by mutation in somatic cells, not usually inherited (may have genetic predisposition) o   Caused by uncontrolled cell division o   Genetic disease at the cellular level o   More than 100 kinds are known §   Usually grouped by cell type it originates in o   Characteristics: §   Originate in single cell •   Clonal §   At the cellular and genetic levels, it is usually a multistep process •   Begins with precancerous genetic change (benign growth) •   Additional genetic changes cause progressive cancerous cell growth §   Once cell becomes malignant, the cells are invasive and causes problems •   Can travel through bloodstream to the rest of body à metastatic o   Cancer can be caused by viruses §   Not very common §   Transformation: process of converting a normal cell into a malignant cell §   Typically, cancer-causing viruses are not very potent at inducing cancer because they are inefficient at transforming o   Oncogenes: Promote abnormal cell growth §   Gain of function mutation §   Cell cycle is regulated by growth factors •   Initiate cascade that causes cell division •   Growth factors can mutate to become oncogenes •   Mutation will cause cell to think growth factor is present when it isn’t §   Proto-oncogenes: normal cellular genes that can mutate to become oncogene •   Expression becomes abnormally active o   Gain-of-function mutation •   Three ways this can occur: o   Oncogene can be overexpressed o   Oncogene can produce aberrant protein that is overly active o   Oncogene may be expressed in cell type where it is not normally expressed •   Mutations can convert normal ras into oncogenic ras o   Keep Ras in active state constantly (cell doesn’t stop dividing) o   Can also decrease the GTPase activity o   Or increase the rate of ADP/ATP exchange •   Proto-oncogenes can be converted into oncogenes in in four ways o   Missense mutations §   convert ras genes into oncogene §   Can be caused by carcinogens o   Gene amplification o   Chromosomal translocations §   Cause expression in cells where it shouldn’t be §   If you know enough about cancer, you can create drug to block that action o   Viral integration §   Can integrate into host DNA as part of their life cycle §   Causes enhanced activation o   Tumor suppressor genes: §   Prevent proliferation of cancer cells •   If inactivated (loss of function), cancer cells are not suppressed •   TS gene can inhibit activator •   First identification of a human tumor-suppressor gene involved studies of retinoblastoma o   “two-hit” hypothesis: a heterozygote has one normal copy and one defective copy of rb gene and in the retina of the eye, the patient suffers a second hit that makes the normal copy defective, giving them retinoblastoma o   when both copies of the Rb protein are defective, the E2F protein is always active, leading to uncontrolled cell division §   P53 Gene: Master tumor suppressor •   50% of all human cancers are associated with defects in the p53 gene •   Primary role of p53 is to determine if a cell has incurred DNA damage or not o   If so, p53 will promote three types of cellular pathways to prevent the division of cells with damaged DNA §   Activates genes that arrest cell division and generally repress other genes that are required for cell division §   Activates genes that promote DNA repair §   Activate genes that promote apoptosis •   Programmed cell death §   General Roles: •   Can have direct effects on negative regulation of cell division •   Can play role in maintenance of the genome §   Loss means no surveillance on cell integrity (not cancer causing!) •   P53 can no longer monitor mutations §   Function of tumor-suppressor genes can be lost in three ways: •   Mutation in tumor-suppressor gene itself o   Promoter could be inactived o   Early stop codon •   DNA methylation o   Methylation of CpG islands near the promoters of tumor-suppressor genes, which inhibits transcription •   Aneuploidy o   Chromosome loss can contribute to cancer progression if the chromosome carries at least one tumor suppressor gene §   Most cancers involve multiple genetic changes •   Can keep making changes after initial cancerous mutation, which leads to malignancy •   Often is a progression of mutations (random order) that accumulate and make the cancer difficult to treat o   Inherited forms of cancer §   Often involve germ-line mutations (5-10% of all cancers) •   Offspring have higher chance of developing cancer because of their inherited predisposition §   Most inherited forms of cancer involve a defect in tumor suppressor genes §   Predisposition is often result of being heterozygous for one of the genes §   Cancer results from loss of normal copy •   Known as loss of heterozygosity (LOH) •   Inherited in dominant manner •   Can result from a point mutation in the normal allele •   Can also occur if chromosome carrying the good copy is lost -   Personalized Medicine o   Use of patients genotype to select treatment suited for patient o   Can be used to choose the best treatment for cancer or to determine best drug dosage o   Molecular profiling §   Using various methods to understand molecular changes behind a disease §   Allows: •   Differentiation between cancers which might look similar under a microscope •   Predicting which drugs target altered genes §   DNA microarray can be used for molecular profiling §   Hopefully allows researchers to find drug targets •   Want to target over expressed genes o   Pharmacogenetics §   Drugs can have very different effects in humans dependent on: •   Rate of transport from digestive track or into target cells •   Ability to affect target protein •   Ability to be metabolized by the liver •   Rate of excretion of drug from body §   Lots of variety among people


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