High-Throughput Sequencing of DNA

Instructor: Giulietta Spudich

Giulietta has taught college students, graduate students and researchers in scientific topics from genomics to biochemistry. She has a PhD in Molecular and Cell Biology.

New sequencing methods have revolutionized the study of genomes. Find out how new technology and computer power are enhancing our understanding of genomes worldwide.

The mystery of DNA

The Genome

A genome is made of DNA and can be thought of as a series of 'letters' (the nucleotides A, T, G and C), which form 'words' (like genes and regulatory regions) that determine, in part, an organism's traits, or phenotypes. Traits encoded by the genome range from benign (e.g., hair color) to more dramatic (e.g., likelihood of contracting diabetes). If scientists and physicians could read a person's genome and understand risk factors for diseases, it would have positive implications for understanding and maintaining one's health. Understanding the genome would also make it easier to tailor medicines and treatments for people, based on what works for a person carrying particular sequences.

There is a lot of natural variation in a genome. These are changes in the nucleotides (for example, some people have an A instead of a G in a specific position in a particular gene). Sometimes variation leads to a change in trait, and sometimes it has no observable effect. So a first step in understanding the important bits of a genome is to find out which base pair changes lead to changes in traits, and which base pair changes are neutral, without consequences.

To determine the natural variation in a genome, scientists would ideally sequence millions of genomes and compare them. In the past, for decades, the only way to sequence genes was Sanger sequencing, developed by Nobel Prize winner Frederick Sanger.

Frederick Sanger
Fred Sanger

Sanger sequencing is still used, but it is very slow and not meant for large-scale genome sequencing. This is where High-Throughput Sequencing (HTS) comes in.

What is High-Throughput Sequencing?

Illumina Sequencing Machine
Illumina Sequencing Machine

HTS methods were developed in the new millennium, and include Illumina, 454 and Ion Torrent sequencing. They are also referred to as Next-Generation Sequencing methods. Thousands to millions of sequencing reactions can be run at once with these approaches, but there are a few drawbacks. HTS has a high error rate, and as HTS generates sequence fragments only, a template must be used - i.e., a known genome sequence to align the sequence fragments to.

However, the benefits of HTS are outstanding. HTS is fast, cheaper than traditional DNA sequencing methods, and generates a massive amount of data. For example, the first human genome sequence generated by the Human Genome Project using Sanger sequencing took over a decade and cost billions of dollars. Sequencing a human genome with HTS methods can cost as little as $1,000 and take only a few months. This means the number of genomes that can be sequenced has dramatically increased. Through 2014, an estimated 228,000 human genomes have been sequenced.

Genome Projects

HTS methods have contributed much to our understanding of genomes already. The 1000 Genomes Project and ENCODE map out variation in genomes across human populations to understand what variations leads to different traits. The 100,000 Genomes Project by Genomics England aims to link variation and disease by combining medical records with genomic information.

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