Human chromosome 4 sequencing and stngle nucleotide polymorphism (SNP) analysis of an achondroplasia individual

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Date
2011
Authors
Ling Sze, Lee
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Abstract
Achondroplasia is the most common cause of short-limbed dwarfism in humans, affecting 250,000 individuals worldwide. This genetic disorder results in various social and medical complications. The majority of achondroplasia cases is sporadic and result from de novo mutations. This autosomal-dominant disorder is caused by single nucleotide mutations in the gene encoding the type 3 receptor for fibroblast growth factor (FGFR3). Tlus study focused on understanding the genetic basis of achondroplasia by identifying SNPs from flow-sorted human chromosomes of an achondroplasia volunteer of Asian origin. Chromosome staining and the bivariate flow karyotyping of human chromosomes were successfully optimized. Whole Genome Amplification (WGA) was carried out to generate high-throughput sequencing data. Thorough analysis of the sequence data and SNPs was unable to identify any known mutations of achondroplasia and hypochondroplasia. Thus, it indicates that the classical achondroplasia indicator gene,fgfr3, may not be the only indicator in this particular case. Why am I different? Living as a shorter person in a world that's designed for the tall people- Why am I different?- is the most frequently asked question I always have. I look different. Everywhere I go, I attract curiosity and I get stared at a lot. As far as I know, I have what I think is an ordinary life. I live with my parents and two sisters. I do not notice the little things that I have to do differently from other people. I felt that I am a normal person, living a normal life. I eat, sleep, breathe, study and get ill, just like everyone else. But why am I still different? I know that some little people like me have a lot of health problems. Personally, I have walking problems and get more back and joint pain than others my age but this certainly is not enough to stop me to go for sports or activities that I enjoy. Thus, I want to change the lifestyle of a little person, who have more serious health problems than I do, to enable them to lead a normal life like other people. As Nobel laureate Paul Berg of Stanford University mentioned before ''All human disease is genetic in origin." So, ho\V do I investigate the mystery c f the genes that made me different and find the answer to my question? Since the completion of the Human Genome Project, the sequence of the human genome is providing the complete view of the genetic heritage. The human genome, the complete set of human genes, comes in 23 separate pairs of chromosomes. If a human genome is a book, then every human being has a story to tell. Each book comes in 23 chapters, which are called chromosomes. Each chapter contains stories, called genes. Here, I will be telling you the story of one of the chapters in my book, chromosome 4, and focusing one of the stories, the fgfr3 gene that is related to a one of the best-known genetic diseases, Achondroplasia. Single-nucleotide polymorphisms (SNPs) are one-base variations m DNA sequence. Each person's genetic material contains a unique SNP pattern that is made up of many different genetic variations. Most SNPs are not responsible for a disease state. Instead, they can often be helpful when trying to find genes responsible for inherited diseases and serve as biological markers for pinpointing a disease on the human genome map. Occasionally, a SNP may actually cause a disease. Therefore, it can be used to search for and isolate the disease-causing gene. Achondroplasia has been mapped to the tip of the short arm of chromosome 4. So, how can we better understand this genetic disorder? There are two possible ways: 1. Sequence a full human genome and analyze the presence of SNPs, or 2. Study chromosome 4 in-depth and compare the SNP patterns between individuals affected by achondroplasia and individuals unaffected by the genetic disorder. At the moment, since achondroplasia-associated mutations are already known to be located in chromosome 4, I will first study specifically chromosome 4 to identify SNPs that could be related to the achondroplasia disease family. Now, how can I identify and isolate chromosome 4 from the 23 pairs of chromosomes? One possible way is to use a rapidly developing technique in research and clinical practice, the flow cytometry and sorting instrument. The flovv cytometry technique enables us to isolate the desired chromosome from the other chromosomes. Directly after isolation, the flow-sorted chromosomes can be sequenced to determine the nucleotide sequence. As human DNA sequences are 99.9% identical to each other, the 0.1% of variation can provide many clues to many diseases and common illnesses. The identification of such variations can help explore the mystery of achondroplasia.
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Chromosome , Nucleotide polymorphism
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