All about genes
Directions: After students have had a chance to review the article “An open book,” lead a classroom discussion based on the questions that follow.
BIOLOGICAL AND CHEMICAL SCIENCES
1. What is DNA?
Genes in cells (everything from bacteria to human cells) are composed of deoxyribonucleic acid (DNA). DNA typically exists as a double-stranded helix, and each strand is a polymer made of a sequence of monomer nucleotides. Nucleotides are chemicals that, like rungs on a ladder, link up the two strands that make up DNA. The nucleotides in DNA are adenine (A), thymine (T), cytosine (C) and guanine (G). A links with T, and C links with G to form DNA. In order for DNA to replicate, the two strands are pulled apart by an enzyme called DNA helicase. Then, other enzymes called DNA polymerases use the original strands as a template to knit together nucleotides to form new complementary strands. This results in two complete DNA double-stranded helices.
2. What is RNA?
RNA, or ribonucleic acid, is chemically very similar to DNA but less stable. Therefore, RNA degrades more rapidly than DNA and is also more prone to mutation. RNA is typically single-stranded, except for short regions (typically 20 nucleotides or less) where one RNA strand folds to bind to itself or to another RNA segment. Similar to DNA, each RNA strand is a polymer composed of nucleotides: adenine (A), cytosine (C), guanine (G) and uracil (U), the RNA analog of thymine. Two strands of DNA and/or RNA can be complementary: Each A on one strand pairs with a T or U on the other strand, and each C on one strand pairs with a G on the other strand. There are various types of RNA in cells, including messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA) and small interfering RNA (siRNA), and all do different jobs.
3. What do genes produce, and how is gene activity controlled?
In cells, genes produce proteins through two processes called transcription and translation. The amount of proteins that genes produce, called gene expression, is controlled by specific sequences in the DNA and RNA, and by various enzymes.
In transcription, certain polymerase enzymes copy genes in DNA or RNA to produce complementary RNA strands. Some of these RNAs include rRNA, tRNA and mRNA. rRNA, tRNA and mRNA are involved in a second process called translation.
During translation, large enzymes called ribosomes (made of both rRNA and proteins) read the mRNA nucleotide sequence and use tRNA to knit together amino acids in a particular order to make a protein. Each codon, or set of three nucleotides, specifies one amino acid. Most amino acids are encoded by several codons. Special codons tell the ribosomes where a protein should begin and end.
4. What types of gene mutations make a normal cell become a cancer cell?
Cancer cells continually divide to produce more copies of the cancer cells, unlike normal cells that only divide when they need to. In order to become a successful cancer cell, typically a cell must: (1) Acquire mutations in its signaling pathways that sense whether and when the cell should divide, converting proto-oncogenes to oncogenes and making the cell think it should always divide. Proto-oncogenes are healthy genes whose protein products help control when cells divide. Oncogenes are mutated versions of proto-oncogenes whose protein products are stuck in the “on” position, always telling cells to divide. (2) Acquire mutations that knock out tumor suppressor genes. Proteins made from tumor suppressor genes normally cause an abnormal cell to repair its DNA or self-destruct. (3) Evade the body’s immune system by altering certain genes or gene regulation, covering the cell surface with sugars to throw off immune system cells or using other tricks.
5. Use the National Center for Biotechnology Information website: https://www.ncbi.nlm.nih.gov or other resources to look up some of the genes that are noted on the human chromosomes in the “The list” diagram in “An open book.” What roles do those genes or their products normally perform, and what diseases might result if the genes are mutated?
BRCA1 on chromosome 17 and BRCA2 on chromosome 13 are both tumor suppressor genes. BRCA1 and BRCA2 proteins help to detect and repair damaged DNA. Mutations that reduce or eliminate the effectiveness of these genes can increase the risk of breast cancer or other forms of cancer.
RB1 on chromosome 13 is another tumor suppressor gene. Its protein product helps to stop uncontrolled cell division. Mutations that reduce or eliminate the effectiveness of RB1 increase the risk of various forms of cancer, including retinoblastoma, for which the gene was originally named.
APC on chromosome 5 is another tumor suppressor. Its protein product helps cells to sense when they contact other cells so they know when to stop dividing. Mutations that reduce or eliminate the effectiveness of APC are associated with increased risk for colon cancer.
LDLR on chromosome 19 encodes the low density lipoprotein receptor protein that helps cells import cholesterol. Certain mutations in LDLR are associated with an increased risk of coronary artery disease.
6. How can gene therapy be used to change DNA in a cell? What are some of the current limitations of gene therapy?
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 is a technique for genetically engineering cells. It has been adapted from natural enzymes that bacteria use to defend against viruses. For genetic engineering, the Cas9 DNA-cutting enzyme is paired with a guide RNA sequence corresponding to the desired target DNA sequence within cells. If the Cas9 protein and guide RNA are introduced into a cell, they can seek out the target DNA and cut it. Cells can repair the break by gluing the cut ends back together, or by pasting in another piece of DNA. Using CRISPR/Cas9, it is possible to delete, replace, mutate or add genes to DNA.
It is easier to do gene editing in smaller numbers of cells in a laboratory than in a patient. Germline gene therapy is used on germ cells — sperm, eggs or fertilized eggs. In this case, genetic changes can be passed down to a person’s future children. But germline gene therapy is highly controversial and not widely used. Somatic cell gene therapy makes genetic changes to non-germ cells and thus would not be passed down to the patient’s children. Somatic cell therapy is much easier to do if cells can be temporarily removed from a patient, treated with gene therapy in a lab, and then reintroduced in the patient. Gene therapy of somatic cells while they remain inside a patient can be done, but it is harder to ensure that enough of the intended cells are treated.
Gene therapy methods are still being developed and may have potential limitations. For instance, a patient’s immune system might attack the virus that delivers the therapy (called a vector) or a patient’s treated cells. Non-therapeutic genes that remain in the vector and are necessary for its function might produce symptoms of infection, trigger unwanted cell division (cancer) or cause other problems. New DNA that integrates in the wrong place might damage an important, previously healthy gene. New DNA that integrates in the wrong place might also trigger unwanted cell division (cancer). CRISPR-based methods might accidentally target the wrong gene some of the time.
ENGINEERING AND EXPERIMENTAL DESIGN
1. Describe a method for sequencing DNA. Are there multiple methods for sequencing DNA?
Over the last several decades, most DNA has been sequenced using a method originally developed by and named after Frederick Sanger. Sanger sequencing uses four separate DNA synthesis reactions — one for each type of nucleotide (A, C, G or T). Each reaction uses normal nucleotides as well as a chemically modified version of one of the nucleotides. As the reactions proceed, double-stranded DNA is pulled apart. Each strand acts as a template that enzymes use to build new strands. Polymerase enzymes make new strands of DNA by adding nucleotides together in an order that complements the template strands. But when a chemically modified nucleotide is added to a strand, synthesis stops. The resulting DNA fragments vary in length. Those DNA fragments can then be loaded into gel and, using electricity, separated by size (which corresponds to one of four nucleotides). Scientists can determine the DNA’s sequence from patterns in the gel. But there are now many more DNA sequencing methods. Some methods pass a single strand of DNA through a pore and sense the different types of nucleotides as the bases go by. Another method lets the DNA bind to short complementary segments and deduces the complete DNA sequence from all of those small segments. Other approaches detect which type of nucleotide a polymerase wants to add to a strand of a certain length, and therefore what nucleotide is in that position. Still others cut DNA at certain nucleotides or into short sequences from which scientists can deduce the complete sequence. Many other methods are in use or under development that could make DNA sequencing faster and more inexpensive.
2. List some ways that DNA sequencing is currently used.
Preventing fraud by checking that the identity of an imported food, such as tuna, matches the label. Analyzing prospective pets to determine what health problems the pets may develop. Checking your own DNA and the DNA of your partner for gene variants that may raise the risk of developing certain diseases or have implications for the health of your future children. Identifying criminals and people who have died.
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