Demand for fast, inexpensive, and accurate DNA sequencing data has led to the birth and dominance of a new generation of sequencing technologies. So-called "next-generation" sequencing technologies enable rapid generation of data by sequencing massive amounts of DNA in parallel using diverse methodologies which overcome the limitations of Sanger sequencing methods used to sequence the first human genome. Despite opening new frontiers of genomics research, the fundamental shift away from the Sanger sequencing that next-generation technologies has created has also left many unaware of the capabilities and applications of these new technologies, especially those in the clinical realm. Moreover, the brisk evolution of sequencing technologies has flooded the market with commercially available sequencing platforms, whose unique chemistries and diverse applications stand as another obstacle restricting the potential of next-generation sequencing. This review serves to provide a primer on next-generation sequencing technologies for clinical researchers and physician scientists. We provide an overview of the capabilities and clinical applications of DNA sequencing technologies to raise awareness among researchers about the power of these novel genomic tools. In addition, we discuss that key sequencing principles provide a comparison between existing and near-term technologies and outline key advantages and disadvantages between different sequencing platforms to help researchers choose an appropriate platform for their research interests.
"Sequencing the human genome was only a short time ago considered the “Mount Everest” of medical achievement. Today, sequencing an entire individual’s genome is widely available and can be performed in a day (rather than years) for thousands (rather than millions) of dollars.1 In a similar manner, technology surrounding preimplantation genetic screening (PGS) has advanced greatly in recent years. "
[Show abstract][Hide abstract] ABSTRACT: The past several decades have seen tremendous advances in the field of medical genetics. The application of genetic technologies to the field of reproductive medicine has ushered in a new era of medicine that is likely to greatly expand in the coming years. Concurrent with an in vitro fertilization (IVF) cycle, it is now possible to obtain a cellular biopsy from a developing embryo and genetically evaluate this sample with increasing sophistication and detail. Preimplantation genetic screening (PGS) is the practice of determining the presence of aneuploidy (either too many or too few chromosomes) in a developing embryo. However, how and in whom PGS should be offered is a topic of much debate.
[Show abstract][Hide abstract] ABSTRACT: Patients with developmental disorders often harbour sub-microscopic deletions or duplications that lead to a disruption of normal gene expression or perturbation in the copy number of dosage-sensitive genes. Clinical interpretation for such patients in isolation is hindered by the rarity and novelty of such disorders. The DECIPHER project (https://decipher.sanger.ac.uk) was established in 2004 as an accessible online repository of genomic and associated phenotypic data with the primary goal of aiding the clinical interpretation of rare copy-number variants (CNVs). DECIPHER integrates information from a variety of bioinformatics resources and uses visualization tools to identify potential disease genes within a CNV. A two-tier access system permits clinicians and clinical scientists to maintain confidential linked anonymous records of phenotypes and CNVs for their patients that, with informed consent, can subsequently be shared with the wider clinical genetics and research communities. Advances in next-generation sequencing technologies are making it practical and affordable to sequence the whole exome/genome of patients who display features suggestive of a genetic disorder. This approach enables the identification of smaller intragenic mutations including single-nucleotide variants that are not accessible even with high-resolution genomic array analysis. This article briefly summarizes the current status and achievements of the DECIPHER project and looks ahead to the opportunities and challenges of jointly analysing structural and sequence variation in the human genome.
Human Molecular Genetics 09/2012; 21(R1):R37-44. DOI:10.1093/hmg/dds362 · 6.39 Impact Factor
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