Whats in a genome? by Cemile G.

Guldal As the buzz of personalized medicine gets louder and individualized medicine centers continue to crop up all over the country, it is no surprise that there is sustained interest in next generation sequencing (NGS). Those who have been following the advances in sequencing technologies ever since the publication of the first human genome the entirety of an individuals hereditary material probably already know about NGS. But for the rest of us, it is hard to understand the hype. To appreciate NGS and the promise it holds, we need to first understand what a sequence is. DNA, the basis of the hereditary information in our cells, is made up of four types of building blocks, which are conveniently named A, T, G, and C. It is the way these molecules are strung together that makes the DNA biologically meaningful. The order in which the letters make up the DNA, that is, the sequence, determines how the resulting molecules will turn out. The molecular machinery in our cells reads this sequence and manufactures the proteins, enzymes, and hormones accordingly, which go on to help cells grow and organs to function. Since the sequence of DNA is so important, any mistakes or changes can lead to broken, unstable, or even harmful proteins and enzymes. Since the 1970s, scientists have been able to determine the sequence of a particular DNA molecule. Since then, sequencing DNA has become faster and cheaper, but accurately and efficiently sequencing a whole complex genome, like the human genome, is still a challenge. With the rise of second-generation sequencing methods, the myth of the cheap genome has lured many scientists and companies to develop progressively better techniques. The three leaders of second-generation sequencing, where DNA can be sequenced in automated machines with the help of lasers, are Roche, Illumina, and Applied Biosystems. But they are already being challenged by the next next generation sequencers, i.e. the third generation sequencers, such as Pacific Biosciences and VisiGen Biotechnologies, which aim for faster and more reliable results with single molecule and nanotechnology methods. As companies aim for better and faster technologies, the price tag of a whole genome sequence has drastically decreased. However, at over $10,000 per genome, everyone agrees that there is room for further improvement. The involvement of the leading biotech companies clearly indicates the financial and scientific interest in using NGS to understand human disease at the DNA level. However, it is not so simple to know what is a mistake in the DNA sequence and what constitutes a simple, harmless variation. A mistake can cause cells to acquire new identities, grow uncontrollably, or die unexpectedly, leading to disease. As a result, most NGS efforts are directed toward catching the mistakes that lead to different diseases, prevent the effectiveness of treatment, or make certain individuals more susceptible to environmental elements that contribute to disease. Determining the mistakes in the DNA sequence may be very useful in making decisions in treatment and disease management in the clinic, but it is not the answer to all the challenges that medicine faces today. There is a variety of ways in which disease can occur; mistakes in the DNA is only one of them. In addition, research has shown that some diseases occur due to very small, hard-to-detect DNA changes in a vast number of genes. Thus the idea that mistakes in a few genes cause a disease is an oversimplification.

Trying to decipher the significance of mistakes in many genes requires a very large number of genomes to be sequenced. Nevertheless, we are sure to reach a point in the near future when we will be able to sequence and analyze a large number of genomes to reveal disease complexities at the DNA level. Scientists who are a part of large NGS-based initiatives such as The Cancer Genome Atlas and The Cancer Genome Project, as well as biotech companies interested in taking a bite out of the personalized medicine pie, envision a day when you walk into your doctors office, give a blood sample, and get your entire genome sequence within hours, complete with annotated disease risk indicators. However, a pressing question remains: how expensive will it be and who will foot the bill?