molecular class 8

Lecture 8: Omics I - Genomics 

Omics are large biological data sets, which can be genomics (genes), transcriptomes (RNA), proteomics (proteins), epigenomics, and metabolomics. Databases on slide- not for test. During corona, omics were used to make a vaccine quickly. Just one month after corona was identified, the entire virus had been sequenced (genomics). They tried to identify which proteins the virus produced and brainstormed what could be delayed to try and stop it. Next, transcriptomics showed RNA of both virus and cell, which also explains how the cell responded to the viral attack and the RNA contents of the virus. Proteomics showed all the proteins produced by the virus, and then metabolomics showed the smaller metabolites. In five months, all of these aspects were understood, thanks to technologies of the human sequencing project. 

The first sequencing was developed by Sanger (bacteriophage → bacteria → yeast → C. Elegans → A. thaliana plant → Drosophila → humans in 2013. The human genome has 3 billion bases, with around 20,000 of these coding for proteins (meaning 1-2% of the human genome codes for proteins). 

Genomics shows that having a higher number of genes does not necessarily make the organism more complex (the lungfish has the largest genome, and the amoeba genome is x200 the size of the human genome). It is used to study how the genome functions, participates in acceleration of technology (NGS), and identifies genetic variants that increase risk of specific diseases. 

All animals have genes for olfactory scenes, but apes and monkeys (especially humans) have the most defective senses of smell. Differences are tails, ability to stand on legs, and intelligence. Most mammals have a thousand closely related genes for olfactory receptors. In mice, all of these genes are intact and functional, compared with 50% in chimps/gorillas and 30% in humans. Genome sequencing of many mammalian species revealed these differences. 

Sanger Sequencing allowed for transcription of relatively large molecules (1,000 bases) but it was pretty expensive. Since we wanted to sequence many genomes very quickly, cheaper methods were developed. The genome is large, and cannot all be sequenced at once. Next Generation Sequencing developed a method of fragmenting DNA into pieces 300 bases long, and used the overlap of these areas to map the genome. Adaptors are added DNA from different genes, which helps it bind to chips. A PCR reaction is carried out so that every time a base is absorbed a different color is emitted per base. A camera shows the bases that were emitted and also how many times they appeared. Gene sequencing is done, for example, on people with certain diseases to try and identify a genetic component, or to find a common ancestor. An example of this was with a rare pediatric liver cancer; a highschool student in remission recruited patients (15) and sequenced their genomes. They all had similar genetic changes that were identified as being responsible for the disease. Genome sequencing has helped us find causes for diseases (specific mutations give diagnosis and prognosis), reactions to treatments (since we have more information about other people), risk predictions, drug repurposing (complex diseases will be more difficult to repurpose than homogenous diseases), driver and passenger mutations (by seeing how frequently certain genes appear), hopes of creating personalized medicine. This would allow use of an individual’s genetic and epigenetic information to tailor drug therapy or preventative care using a combination of many fields. For example, cystic fibrosis has many different mutation options for the CFTR channel that causes the disease. Ivacaftor works on a specific type of mutation that decreases the channel’s activity- it will only help if the patient carries the exact mutation that causes a specific loss of function. This is also true for cancer; Herceptin can only be given to breast cancer patients with HER-2/neu receptor mutation. Patients can have different mutations even in the same biological pathway. For example, the RAS mutation status affects patient management not as a drug target but as a resistance marker for a tumor’s responsiveness to EFGR (anti-epidermal growth factor receptor) therapies. Erbitux for colon cancer can only be given to patients without the EFGR mutation (binding causes RAS, which tells the cell to divide), and binds the receptor to inhibit it. Patients that carry a mutation in the channel will not respond to the medication, since the signal for proliferation does not come from the channel, so stopping the channel does not affect proliferation. Sequencing of resistant patients revealed that these patients did not respond to the medication. Only EFGR mutation testing is now recommended before patients start treatment.