CHAPTER 19 THE ORGANIZATION AND CONTROL OF EUKARYOTIC GENOMES => Larger than prokaryotes Not all 25,000 genes are active in all cells Junk DNA anyone? Only 25,000 genes in humans - 3%
of total DNA in cell (YIKES!) Rest of it (97%) junk????? (noncoding DNA) Prokaryotes- most of the DNA in a genome codes for protein (or tRNA and rRNA), with a small amount of noncoding DNA, primarily regulators. Eukaryotes - most of the DNA
(about 97% in humans) does not code for protein or RNA. 96% similar to human s) Noncoding DNA and what it does in the eukaryotic genome 1) Some noncoding regions
are regulatory sequences (these are promotors and enhancers that can increase binding of RNA polymerase to DNA). 2) Other are introns. 3) Finally, even more of it consists of repetitive DNA, present in many copies in the genome.
REPPPPETITIVE DNA IN EUKARYOTES Know 2 types of Repetitive GTTACGTTACGTTAC. DNA: repeated 10 to 10 million times (Satellite DNA) 1)TANDEMLY REPETITIVE DNA (AKA SATELLITE DNA - *3 types) - 10 to 15% of DNA 2) INTERSPERSED
REPETITIVE DNA - 25 - 40% of DNA REPPPPETITIVE DNA IN EUKARYOTES 1) SATELLITE DNA/TANDEMLY REPETITIVE DNA These sequences (1 to 10 base pairs) are repeated up to a million times in series. GTTACGTTACGTTAC. 3 types: a) Regular Satellite -100,000 - 10 mill
b) Minisatellite -100 -100,000 repeats c) Microsatellite - 10 to 100 repeats Very important for forensics - helps figure out uniqueness of a persons DNA A number of genetic disorders are caused by abnormally long stretches of tandemly repeated nucleotide triplets within the affected gene. CAG
Repeat CAG Repeat Size Median Age at Onset * (years) (95% confidence interval) 39 66 (72-59)
40 59 (61-56) 41 54 (56-52) 42 49 (50-48)
43 44 (45-42) 44 42 (43-40) 45 37 (39-36)
46 36 (37-35) 47 33 (35-31) 48 32 (34-30)
49 28 (32-25) 50 27 (30-24) You know that antisocial neighbor May be a microsatellite problem Satellite DNA plays a structural role at
telomeres and centromeres. This is important! You dont want nonrepetitive DNA in telomeres because? CSI Lab on this coming upMicrosatellites more repeats but really short! Are only 1-10 nucleotides long and are repeated only 10-100 times in the genome Used in DNA fingerprinting
(forensics) What, more junk? (2) About 25-40% of most mammalian genomes consists of interspersed repetitive DNA. -One common family of interspersed repetitive sequences, Alu elements, is transcribed into RNA molecules with unknown roles in the cell. -Alu sequences may help alternate RNA splicing
-Transposons are interspersed repetitive DNA Table 19.1 bottom Out of 25,000 genes what gets expressed depends upon: Type of cell: Not all genes are expressed in all cells (epigenetics
controls it) Development period: During embryonic development certain genes may be expressed that are not expressed in adults (and viceversa) Gene families - collection of genes that may be identical/nonidentical
evolved by duplication of ancestral genes Most genes are present as a single copy per haploid set of chromosomes Multigene families exist as a collection of identical or very similar genes (exceptions). These likely evolved from a single ancestral gene. The members of multigene families may be clustered or dispersed in the
genome. Identical genes are multigene families that are clustered tandemly. Evolution - first duplicate a gene and then mutate the copy; result : original copy is still there, mutated gene could make a new protein = new function (natural selection acts on it) Nonidentical have since
theirtoinitial PseudogenesDNAgenes segments thatdiverged have sequences similar real genes event. butduplication that do not yield functional proteins - remnants of evolution or?
changes continually in your lifetime? 1) Rare mutations (between 1/106 and 1/105 nucleotides ) 2) Gene amplification selective DNA replication of some genes to increase protein expression (ex. after chemotherapy) 3) Transposons/ Retrotransposons(Jumping genes) 50% - Corn 10% Human
during your lifetime? continued Rare mutations Gene amplification temporary increase (selective loss also possible) in number of gene copies Transposons and retrotransposons Gene rearrangement in Immunoglobin Fig. 19.5
genes B lymphocytes (WBC) produce immunoglobins, or antibodies, that specifically recognize and combat viruses, bacteria, and other invaders. -Millions of types of Antibodies can be produced depending on what the infectious agent is how? -Immunoglobins have constant and variable region -100s of gene segments code for the variable region of the
antibody. -DNA segments are put together to create an endless combination of constant and variable regions - gene rearrangement occurs in your lifetime! TRANSLATION TRANSCRIPTION Promotor
RNA Polymerase makes premRNA using the elves transcription factors (proteins) Many protein factors are involved in translation as well How is gene expression controlled? That is = if/what protein is made? How can you control this?
Levels of control goals.. 1) Changing DNA physically => mRNA making affected 2) Changing access to DNA Promotor 3) If mRNA is made; How long mRNA hangs around; change which protein is made from one mRNA - (splicing); dont use the mRNA 4) Change/destroy the protein after its How is gene expression controlled in you? (IMPORTANT)
When is the gene active (on or off)? That is what protein is made? How can you control this? Gene expression control = which genes are on Levels of control 1) chromatin (DNA) packing and chromatin modification - change access sites on DNA for RNA Polymerase so that its binding decreases/increases (epigenetics layer of control above the genome - NOVA Video) 2) Transcription - when DNA makes mRNA 3) Post-transcriptional - RNA processing, translation 4) Post-translational - various alterations to the protein
product. Fig. 19.7 1a) Level of packing is one way that gene expression is regulated. Densely packed areas are inactivated. (Heterochromatin) - during mitosis Loosely packed areas are being actively transcribed. (Euchromatin) - during Interphase
Chromatin structure is based on successive levels of DNA packing INTERPHASE Interphase - chromatin fibers highly extended Mitosis - chromatin coils and condenses to form short, thick chromosomes. MITOSIS
Which stage do you see beads on a string? (Interphase) Histone proteins are responsible Are genes for active? Yes transcribed into mRNA!
the- first level of DNA packaging. Their positively charged amino acids bind tightly to negatively charged DNA. Beads on a string = a nucleosome, in which DNA winds around a core of
histone proteins Next level of packing - 30 nm solenoid fiber nucleosome fiber Has (DNA + HISTONES) with 6 nucleosomes per turn Which stage do you see 30 nm fiber? (Mitosis) Are genes active? - Yes transcribed into mRNA! The 30 nm fiber forms looped
domains attached to a scaffold of nonhistone proteins. Which stage do you see looped domains? (Mitosis) Are genes active? -No 1b) Chromatin modifications (epigenetics)
Chemical modifications of DNA bases: A) DNA methylation is the attachment by specific enzymes of methyl groups (CH3) Inactive DNA is highly methylated compared to DNA that is actively transcribed. Genomic imprinting is related to DNA methylation DNA Methylation - add a methyl group t make DNA less accessible to RNA Polymerase 1b) Chromatin
modifications B) Histone acetylation (addition of an acetyl group -COCH3) and deacetylation Acetylated histones grip DNA less tightly = ? More access to RNA Polymerase! SO,. Epigenetics - DNA methylation and histone acetylation may be responsible for a lot of traits that are not just related to whether you have the gene/not. Example: If your gene is methylated you may never express the trait!
2) Control of Transcription very important - to make or not make mRNA Control elements - noncoding DNA segments that regulate transcription by binding transcription factors that are needed for RNA Polymerase binding. (TATA Box -Promotor, Activators in bacteria - Enhancers in Eukaryotes, Repressors in bacteria - Silencers in Eukaryotes)
How can a DNA control element 100s of basepairs upstream of a gene regulate the access to RNA Polymerase? Bending of DNA enables transcription factors, activators (like steroid hormones), bound to enhancers to contact the complex at the promoter. Mostly positive gene regulation in eukaryotes! Fig. 19.9
The hundreds of eukaryotic transcription factors follow only a few basic structural principles. Each protein generally has a DNAbinding domain that binds to DNA and a protein-binding domain that recognizes other transcription factors. Fig. 19.10 3) Post-transcriptional mechanisms - so mRNA is made, what next?
A) RNA processing alternative splicing controls which protein is made from one mRNA - mix-n-match introns/exons 3) Posttranscriptional mechanisms B) Life span of a mRNA molecule Prokaryotic mRNA molecules degraded by enzymes after only a few minutes. Eukaryotic mRNAs endure typically for hours or even days or weeks.
G L 5 Cap Leader T Trailer AAAAA Poly A tail 3) Post-transcriptional mechanisms C) Translation - can be blocked by regulatory
proteins that bind to 5 leader region of mRNA. (prevents attachment of mRNA to ribosomes) Protein factors required to initiate translation = simultaneous control of translation of all the mRNA in a cell. G L 5 Cap Leader T
Trailer AAAAA Poly A tail 4) Post-translational mechanisms Processing of polypeptides to yield functional proteins. This may include cleavage, chemical modifications, and transport to the appropriate destination.
Regulation may occur at any of these steps. The cell limits the lifetimes of normal proteins by selective degradation. Proteins intended for degradation are marked by the attachment of ubiquitin proteins. Giant proteosomes recognize the ubiquitin and degrade the tagged protein.
Fig. 19.12 CANCER REVIEW- read on your own - use these animations Cancer results from genetic changes that affect the cell cycle Cell cycle CONTROL events dont work Spontaneous mutations or environmental influences (carcinogens)
Cancer-causing genes oncogenes (retroviruses), proto-oncogenes (in other organisms). What happens when protooncogenes/oncogenes are turned ON? (Ras gene) Cell will divide without stopping Malignant cells often have significant changes in chromosomes Fig. 19.13
Are there genes that prevent cancer? Tumor-suppressor genes -normal products inhibit cell division, repair DNA, control adhesion (p53). Mutations to these tumor suppressor genes = cancer Oncogene proteins and faulty tumor-suppressor proteins
The p53 gene, named for its 53,000dalton protein product, is often called the guardian angel of the genome. Damage to the cells DNA acts as a signal that leads to expression of the p53 gene. The p53 protein is a transcription factor for several genes. It can activate the p21 gene, which halts the cell cycle. It can turn on genes involved in DNA repair.
When DNA damage is irreparable, the 3. Multiple mutations underlie the development of cancer More than one somatic mutation is generally needed to produce the changes characteristic of a full-fledged cancer cell. If cancer results from an accumulation of mutations, and if mutations occur throughout life, then the longer we live,
the more likely we are to develop cancer. Colorectal cancer, with 135,000 new cases in the U.S. each year, illustrates a multi-step cancer path. The first sign is often a polyp, a small benign growth in the colon lining with fast dividing cells. Through gradual accumulation of mutations that activate oncogenes and knock out tumor-suppressor
genes, the polyp can develop into a malignant tumor. Fig. 19.15 About a half dozen DNA changes must occur for a cell to become fully cancerous. These usually include the appearance of at least one active oncogene and the mutation or loss of several tumorsuppressor genes. Since mutant tumor-suppressor alleles are usually recessive, mutations must knock out
both alleles. Most oncogenes behave as dominant alleles. In many malignant tumors, the gene for telomerase is activated, removing a natural limit on the number of times the Viruses, especially retroviruses, play a role is about 15% of human cancer cases worldwide. These include some types of leukemia, liver cancer, and cancer of the cervix.
Viruses promote cancer development by integrating their DNA into that of infected cells. By this process, a retrovirus may donate an oncogene to the cell. Alternatively, insertion of viral DNA may disrupt a tumor-suppressor gene or convert a proto-oncogene to an The fact that multiple genetic changes are required to produce a
cancer cell helps explain the predispositions to cancer that run in some families. An individual inheriting an oncogene or a mutant allele of a tumor-suppressor gene will be one step closer to accumulating the necessary mutations for cancer to develop. Geneticists are devoting much effort to finding inherited cancer alleles so that predisposition to certain cancers
can be detected early in life. About 15% of colorectal cancers involve inherited mutations, especially to DNA repair genes or to the tumor-suppressor gene APC. Normal functions of the APC gene include regulation of cell migration and adhesion. Between 5-10% of breast cancer cases, the 2nd most common U.S. cancer, show an inherited predisposition. Mutations to one of two tumor-suppressor
genes, BRCA1 and BRCA2, increases the risk of breast and ovarian cancer.
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