This year (2015) was a dynamic and busy one for the field of next-gen sequencing. We saw the release of a paradigm-shifting sequencing platform, milestone publications of key big science projects, and the sustained acceleration of discovery enabled by high-throughput genomics technologies. Here are some of the things that rocked our world in 2015.

Large-Scale Genome Sequencing

My first post in 2015 was uncannily prescient: it reviewed a study that uncover rare variants associated with myocardial infarction using exome data from NHLBI’s Exome Sequencing Project (ESP). The ESP was a pioneering effort in many ways, and its database of coding variation from thousands of exomes has been a critical resource for many research studies.

One clear trend from this year, however, is that the time of the exome is waning. Later in January, I profiled Illumina’s newest sequencing platforms.  The most significant of these was the HiSeq X Ten, a 10-instrument “factory installation” that enabled the most cost-effective human whole genome sequencing to date: 18,000 genomes per year at a consumables cost of just over $1,000 each (note: this does not include the costs of data storage, analysis, or the $10 million buy-in). Correction: this figure does incorporate the cost of the instruments based on 100% capacity over a period of 4 years. However, I doubt it incorporates the system’s additional $100,000 “shipping & handling” fee.

Chief among the restrictions that accompanied the X Ten was the requirement that X Tens only be used for whole-genome sequencing, and only for human genomes.

The Value of Cohorts

For the first few months of 2015, my world was consumed by our center’s application to the Centers for Common Disease Genomics program from NHGRI. Among many things, it made me appreciate the value of large, diverse, deeply-phenotyped, widely consented sample cohorts for genomics research. And as I pointed out in February, consumer genetics firm 23andMe has one of the largest sample cohorts in the United States. Among the 700,000+ individuals who’ve undergone 23andMe testing are subsets of intense clinical interest, such as Parkinson’s disease patients.

Granted, their research cohort has some caveats to it, not the least of which is the fact that most of the phenotypes are self-reported. Even so, 23andMe made at least two big-money deals with pharmaceutical companies, which suggests that they might be onto something.

Epigenetics and Regulatory Variation

One of my favorite papers from this year was the landmark publication of the NIH Epigenomics Roadmap Consortium, which profiled 111 primary human tissues and cell types for histone modification patterns, DNA accessibility, DNA methylation, and gene expression. The Epigenomics Roadmap, the ENCODE Project, and other functional genomics initiatives are just so vital as we expand our search for phenotypically-relevant variants outside of the coding regions.

Recent forays into the study of regulatory variation have already been promising. Just a few months ago, I reviewed a paper demonstrating that regulatory variation near genes predicts gene dosage sensitivity. More studies like that are bound to come.

Genetic Variation and Human Disease

There were far too many disease gene discovery papers than I could ever hope to cover on MassGenomics, so I admit to playing favorites. I enjoyed showcasing our targeted sequencing study of cleft lip, in which we used model systems in zebrafish and mice to functionally validate rare variants uncovered by sequencing known GWAS loci.

I also reviewed a wonderfully informative study on human de novo mutations in 250 Dutch families sequenced by the Genome of the Netherlands Consortium. My favorite tidbit of this paper was the observation that 75% of de novo mutations come from the father, whose age was correlated not just with the number of de novo mutations, but also their location relative to late-replicating regions of the genome.

In June, I highlighted some of the latest additions to the catalogue of known retinal disease genes, also known as RetNet. Among the many diseases whose genetic underpinnings can be studied by NGS, retinal diseases might be the top beneficiary. In the June update, 278 retinal disease genes had been mapped, including first bona-fide noncoding gene linked to a retinal disease.

Beyond Research: Sequencing in the Clinic

Next-generation sequencing continues to find new clinical applications. Exome sequencing, especially via the GeneDx service, has become a routine diagnostic test. Over the summer, I wrote a post emphasizing the importance of clinical sequence data sharing in repositories like the ClinSeq database, which has already proven life-saving (or life-changing) for thousands of patients and their families. A month later, I covered a paper in Nature Genetics that offered some sound advice on how to succeed at clinical genome sequencing.

My institute and St. Louis Children’s Hospital also launched a new initiative this year, called the Pediatric Genomics Board (PGB), to perform research exome sequencing for infants with severe (but undiagnosed) genetic disorders. I’m therefore excited to see the potential of state-of-the-art sequencing and analysis techniques to determine the molecular cause of such cases.

Personal Highlights for 2015

As the year draws to a close, I find myself grateful, because 2015 has been good to me. I saw my 60th research publication this year, and helped write one of the best grant applications I’ve ever been a part of (look for a press release next month). I got to see Oregon and meet all kinds of nice people when the OHSU Program for Molecular and Cellular Biology invited me to deliver the keynote at their annual retreat. I got to chair an outstanding session on cancer genomics at the ASHG meeting in Baltimore, and I was on TV for almost five minutes! (it was ASHG TV, but that counts in my book).

And speaking of books, I learned that HarperCollins will publish The Rogue Retrieval, my novel about a Vegas magician who infiltrates a medieval world. It comes out January 19th, by the way. If you’ve read this far in my blog post, it’s probably right up your alley.

Thank you for your loyal readership of MassGenomics this year. See you in 2016!