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DNA Sequencing – How and Why Important

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DNA Sequencing – How and Why Important DNA Sequencing – How and Why Important 1977 – Frederick Sanger – dideoxynucleotide sequencing - when incorporated causes chain termination Original Sanger Sequencing Automated Sanger Sequencing Human Genome Project 1990 – funded as 15 year project to determine the nucleotide sequence of the entire human genome 2000 – Rough draft made available 2003 – The project was completed after final editing. Cost: $3 Billion - Identified approximately 23,000 protein coding genes - Fewer than 7 % of proteins are vertebrate specific - Complete data stored on multiple internet sites with tools for visualizing and searching UNDER currents BY KATHARINE MILLER IS CLINICAL GENOMICS TESTING WORTH IT? Cost-efectiveness studies yield answers to the complex question of whether clinical genomics testing has value. hole-genome testing has now variant and the possible benefts of test- to the right patient at the right time. reached the long-anticipated ing—are uncertain. Sequencing also Cost-efectiveness analyses are revealing W “$1,000 genome” level; and provides information about many difer- valuable benefts for certain patients, in more targeted genetic panels cost even ent genes, and each variant will have a the areas of rare pediatric disease, cancer, less. But the costs associated with diferent cost-beneft ratio. “You can’t do and pharmacogenomics. But the jury genomic testing don’t end with sequenc- a holistic view of the full beneft of these is still out as to whether whole exome ing. Additional expenditures—for follow- tests,” says Eman Biltaji, PhD, gradu- or whole genome sequencing (WES or up testing or treatments—may far exceed ate research assistant at the University of WGS) for healthy patients is worth it. the investment in sequencing itself. Utah. “You can only do a study focusing “I hear people say, ‘of course it’s cheaper on one piece of it and then another study Rare Diseases and better to just sequence people up focused on another piece of it.” Finally, in Children: front: More information is better,’” says patients’ preferences and behaviors com- Test Early! Kathryn Phillips, PhD, professor of plicate things. For example, if a patient Children afected by rare monogenic clinical pharmacy at the University of who gets a negative genetic test decides to conditions often undergo an extended California, San Francisco. “In fact, it might forego routine disease screening as a result, diagnostic odyssey during which they be better in some situations but not oth- that could be a hidden cost of testing. are poked, prodded, tested and hospital- ers.” Phillips and others are trying to pin- As payers (insurance companies and ized at great expense to their families point the situations for which the health governmental insurers) weigh whether and the healthcare system. A study of benefts of genomic testing outweigh the to cover the costs of testing or not, 40 such patients published in Genetics costs, using cost-efectiveness analyses. cost-efectiveness research may help in Medicine in January 2017 found that It’s not a simple task: Te inputs—such provide some answers to the key ques- cost-efectiveness was maximized when as the risks associated with a genetic tion: how to deliver the right service patients were ofered WES as soon as a Cost of Sequencing a Human Genome problem was suspected. “If you fnd out what’s happen- ing early in the diagnostic trajectory, it does allow you to infuence management of the genetic disorder a lot more than if you’re provided with an answer a few years down the The cost of sequencing a human genome track,” says Zornitza Stark, has dropped significantly since 2001 and MD, a clinical geneticist at has significantly outpaced Moore’s Law Murdoch Children’s Research since 2008 with the advent of next-gen- Institute in Melbourne, eration sequencing technology. Courtesy Australia, one of the lead of NHGRI, https://www.genome.gov/ researchers on the study. sequencingcostsdata/ Another similar study of 150 pediatric neurology patients in the Netherlands also found early use of WES to be cost-efective; and a Canadian study of 103 pediatric patients with suspected genetic disorders found that WGS provided a Published by the Mobilize Center, an NIH Big Data to Knowledge Center of Excellence 3 Illumina Sequencer – reversible terminators - Fragment DNA, ligate primers, attach in wells of flow cell, and amplify fragments to produce a clonal cluster - Individual reads of 100-400 bases aligned by computer - Current instrument can sequence 45 genomes simultaneously at a cost of $1000 per genome Ion Torrent Sequencing Eukaryotic Genes Contain Exons and Introns Human Genome: Types of DNA Sequences Human Genome: Protein Coding Genes Use of Single Nucleotide Polymorphisms (SNPs) - Sites in DNA where single nucleotide changes occur Identification of Early Onset Alzheimer Gene Haplotypes that correlate with Early Onset Alzheimer's Mutation of the S182 gene causes accumulation of plaques that are associate with Alzheimer’s. The gene encodes a protein now termed presenilin-1. 23 and Me Sequences multiple haplogroups on - Y chromosome: passed from father to sons - Mitochondrial DNA: passed from mother to sons and daughters Use haplogroups that are characteristic of different races or that correlate with mutations that contribute to onset of a specific disease (for example: BRCA1/BRCA2, PSEN1. Short Tandem Repeats used for Forensic Analysis Combined DNA Index System (CODIS) Genetic Fingerprinting amplifies 13 STRs and the Amelogenin gene to identify a unique individual With 13 point match, misidentification is less than 1 in 1018. .
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