RESEARCH STRATEGY
A. SIGNIFICANCE
Charting genetic interactions in a mammalian cell will help us understand normal cell processes. A map of interactions will also pinpoint what goes wrong in diseases like cancer. But deciphering the genetic circuitry of the mammalian cell remains a daunting challenge. One major obstacle to annotating genetic interactions is their number. In a genome of 20,000 genes, there are 2 x 108 possible pairwise interactions. Either gene-gene or protein-protein interactions can be used to unravel molecular networks. In yeast, scientists employ synthetic genetic array analysis to map gene interactions (Costanzo et al., 2010; Tong et al., 2001; Tong et al., 2004). In Caenorhabditis elegans, they use RNA interference
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But only a modest fraction of interactions are tested (Lee et al., 2004; Lee et al., 2008).
Our understanding of mammalian genetic interactions is even less impressive. Large-scale efforts to map the protein interactome in humans have begun (Gandhi et al., 2006). But only about 10% of potential interactions have been evaluated (Rual et al., 2005; Venkatesan et al., 2009). Furthermore, genetic interactions in humans and mammals remain unexplored. The overlap between human, yeast, C. elegans, and fly protein interaction networks is small (Gandhi et al., 2006). Hence, it is necessary to explore mammalian genetic interactions in the mammalian setting. A problem for mammalian cells is the lack of a simple and cheap method for combining alleles of distinct genes in the same cell.
Our hypothesis is that mammalian cells must thrive by exploiting combinations of genes, in fact, genetic networks that both protect the cell from destruction and enhance its survival. We believe these networks involve genes that tend to be coordinated in their copy number alterations (CNAs), even when they are located at a distance on the genome. Our recent work studying genetic networks that exist within libraries of radiation hybrid (RH) cells have elucidated key survival-enhancing interactions with remarkable specificity (Lin et al., 2010). This work identified genetic interactions with close to single gene
The fruit fly, Drosophila melanogaster, became an important model organism for the study of human genetics and for the establishment of more biological principles (Roberts 2006). This organism became a good candidate to work with because of its short life cycle, its inexpensiveness, small size, its genetic variability, easily cultured and its ability to produce many offspring. Nichols and Phandey made an important discovery: approximately 75% of disease-causing genes in humans are homologous to genes found in Drosophila melanogaster (Russell and Tickoo). This is an important observation, because it made it possible to discover treatments for human diseases. For example, the fly has a tumor gene homologous to the human LATS1 gene.
Throughout the years scientists and researchers have done many studies that pertain to how mutagens cause mutations in genes. They have also studied these mutations to see if they transfer to the next generation or whether the DNA repairs the mutation before it gets passed on. In this lab we will be looking at the mutagen ethyl methanesulfonate (EMS) and how it will affect our organism Caenorhabditis elegans (C. elegans). EMS is known to be mutagenic and carcinogenic because it can “produce significant levels of alkylation at oxygens of guanine and in the DNA phosphate groups. It can also produce GC to AT transition mutations and vice versa. There has also been evidence that EMS is able to break chromosomes” (Sega). We hypothesize that when we expose the C. elegans to the EMS, a mutation will occur on the DNA that will cause a phenotype to occur in the organism that is different from the wild type. Our goal is to be able to locate the mutation on a gene, and match it to other kingdoms to see if they are homologous to other genes. This is beneficial to us as humans
One of the main reasons I chose to research this gene is because of its association with
Scientist Christopher Allen, a researcher in the environmental and radiological health sciences department studies the genes that are essential for repairing DNA inside our cells. According to him, when the repair process takes a rouge turn, the result can be cancerous. Allen would like to be able to make a side-by-side comparison with a cell that has a gene he thinks is important in the repair process, and one that is missing that gene. In order to execute this comparability, he has to modify the genome of a cell, which CRISPR-Cas9 is helpful for.
This sequence lets scientists know the character and location of all C. elegans' genes. However, biochemists do not yet fully understand what each gene does and the goal of this experiment is to find the function of each gene within the worm. The connection between a worm's genotype and phenotype is important, because, believe it or not, human beings and worms share many of the same
If the DNA is damaged, it can pass the damage on to new cells
According to Verial (2010), “Studies usually have at least one limitation that makes some aspects of their results less likely to be accurate, such
Integrative Genomics Viewer (IGV) is a visualization tool used in Bioinformatics to explore large-scale genomic datasets.
Skin cells are always being overwhelmed with radiation and certain genes are responsible for fixing the damage. When a gene called ‘patched 1’ (also known as PTCH1) is inactivated it causes an increase in excessive cell growth, also known as cancer. Patched 1 was found in a fruit fly called Drosophila melanogaster and is located on the ninth chromosome in humans. Malfunctioning patched 1 leads to defective embryonic development and many types of skin cancer. Patched 1 is usually born in a somatic cell so inheritance of a
Caenorhabditi elegans?has become an important organism in which to study processes that go awry in human diseases since over 50 yeas ago when Sydney Brenner had the foresight to develop the nematode (round worm)?Caenorhabditis elegans?as a genetic model for understanding questions of developmental biology and neurobiology. There are several attractive features that make Caenorhabditi elegans?an ideal organism for the study of gene regulation and function. First of all, C. elegans is a eukaryote, which means that it shares cellular and molecular structures and control pathways with higher organisms. At least 38% of the C. elegans protein-coding genes have predicted orthologous in the human genome,
Genomic structural variants (SVs), including deletions, duplications, inversions, and translocations of genetic sequences, account for at least five times more variable base pairs than single nucleotide variants among human genomes. However, traditional genome-wide scans for adaptive evolution and disease association tend to ignore thousands of complex structural variants because these scans rely heavily on intact linkage disequilibrium blocks. This is because a majority of deletion polymorphisms in the human genome is not in linkage with single nucleotide variants around it due to frequent gene conversion events in this locus. Recent locus-specific studies have investigated a handful of such complex structural variants and have made
Compelling evidence of shared ancestry in living things is demonstrated in the genetic code. Throughout evolution, life forms develop new genes to support different body changes. Over an organism’s evolution, genes are commonly maintained, however, many complex organisms are capable or retaining various genes from their primitive past. DNA is constantly subject to mutations, or accidental changes in its code. Malformed or missing proteins are consequences of mutations, which can lead to various diseases. Such mutations are an overall history of the evolutionary life of a gene, which can be be caused by cell division or when DNA gets damaged by environmental factors, such as UV radiation, viruses, and chemicals. Although some mutations can be
It is greatly involved in immunity. Mostly in plants, it is greatly involved in the immune response system to prevent viruses and harmful genetic material from damaging the cell. In animals, the RNAi pathway serves an antiviral purpose, providing protection against pathogens, bacteria, and other harmful organisms that could potentially put the cell in danger. Jaronczyk’s findings exaplain that RNAi pathways also play a large role in the regulation of development of cell growth and development. It regulates the timing of morphogenesis, a process which organizes the special distribution of cells during its embryotic development stages. It also regulates the maintenance of undifferentiated cell types, or those who are not yet specialized. Finally, RNAi pathways help in RNA activation, and event in which specific short dsRNA molecules bring about the targeted gene expression. Even evidence of RNA interference pathways are relevant in the everyday lives of humans such as insecticides, genetically engineered foods, and new treatments for cancer as described by Hannon in RNAi: A Guide to Gene Silencing
The Yeast two-hybrid system was used in this investigation to find which of four DNA inserts codes for a protein able to interact through protein-protein interactions with the protein encoded by the Bub1B gene. The protein encoded by the Bub1B gene is a kinase, which has a role in the formation of the mitotic spindle checkpoint ‘Davenporta et al. (1998)’
Regulation of any biological phenotype is a complex and tuned phenomenon (Weng et al, 1999). Biological systems face frequent change in the environment, both at intrinsic and extrinsic levels. These systems have evolved themselves to integrate these fluctuations and take an appropriate decision (Helikar et al, 2008). Classical genetics and DNA sequencing have provided a lot of information about different types of genes and their functions, but how do these genes interact and integrate environmental signals to encode different phenotypic responses, is not clearly understood. Emergence of synthetic biology has enabled biologists to characterize these genetic components in isolation and predict the behavior of complex networks. Synthetic