Gene Patents and Genetic Testing

NOTE: Getting Advice About Genetic Testing

This week, Angelina Jolie wrote an editorial for the New York Times describing how she underwent a double mastectomy after testing positive for a deleterious BRCA1 mutation.

This article stirred up a lot of discussion because she mentions how "[the] cost of testing for BRCA1 and BRCA2, at more than $3,000 in the United States, remains an obstacle for many women".

Although there have been responses pointing out that insurance can significantly decrease the out-of-pocket costs to the patient (under the right circumstances), the question remains "Why is the test so expensive?".  After all, the true cost to perform the test is much less than $3,000.

The genetic test in question is Myriad's BRACAnalysis test.  This company should sound familar because the Supreme Court recently heard a case from Myriad to decide if human genes can be patented (the BRCA1/2 gene patents are the reason why the Myriad test costs so much).

There are lots of resources to learn more about the court case and BRCA testing.  For example, Chris Mason recently wrote good summary on the topic.  However, I want to re-emphasize a couple important points here:

1) It is possible to provide a genetic test covering a panel of diseases at ~1/10th of the cost.  For example, 23andMe provides carrier status for a variety of diseases (including some BRCA1/2 mutations) for $99.  Likewise, Counsyl offers genetic testing that is less than $100 with insurance or less than $1000 without insurance.  There are also various options for discovering mutations in raw sequencing data, whose cost is continually decreasing.

2) The basis of Myriad's claims to retain its patents is the high development costs to develop the test.  Regardless of the ethical arguements against gene patients (and the high likelihood that genetic tests will be based upon findings from government-funded research), this is no longer a technical concern now that the human genome has been sequenced.  There a multitude of freely available tools to help clone any region of the human genome.  There are certainly still novel discoveries out there (like novel non-coding genes, fusion genes, etc.), but I would argue the tricky part is asking the right question - the production of the cDNA is then trivial.  I see no reason why individuals should have to pay for the costs of a patent for the interpretion of a medical discovery reported in the scientific literature.

Bioinformatics 101: Bioinformatics Journals

Here are some of the journals that I check on a weekly basis.  I would strongly recommend subscribing to the relevant RSS feeds (using something like Google Reader).

Bioinformatics / Computational Biology:

• Bioinformatics
• PLoS Computational Biology
• BMC Bioinformatics

Genomics:

• Genome Research
• Genome Biology
• Nucleic Acids Research
• PLoS Genetics
• BMC Genomics

Other Journals:

• Nature Methods and Nature Biotechnology - not specific for bioinformatics articles, but many important programs / protocols are published here
• PLOS ONE - general subject journal, but it has some good bioinformatics articles
• peerJ - similar to PLOS ONE, but utilizes a membership system (so, you pay by author instead of by article)
• Nature, Science, PNAS, etc.

Tutorials / Blogs:

• OpenHelix - tutorials for popular programs; some free, some require subscription
• Open Helix Blog - this covers tutorials and FAQs for common bioinformatics tools. I mostly read it for the Friday SNPpets (collection of popular weekly twitter feeds)
• Omixon Blog - Bioinformatics company that provides free tutorials for common tools
• Core Genomics - "personal blog written by James Hadfield who runs a Genomics core facility Cambridge" - lots of interesting technical details about next-generation sequencing
• MassGenomics - medical genomics blog by Dan Koboldt, a staff scientist at the Genome Institute at Washington University. Consistently great article reviewers.
• Genomes Unzipped - popular blog run by several genomics researchers. I would argue that it was made popular by Daniel McArthur (who doesn't post there as often now), but there are still other contributors that keep the blog up to date.
• Getting Genetics Done - a well-maintained blog written mostly by Stephen Turner (Bioinformatics Core director at University of Virginia). Focuses mostly on providing technical suggestions.
• List of Bioinformatics Workshops
• NIH Bioinformatics Support System - probably doesn't have a feed, but contains useful tutorials

Bioinformatics 101: RNA Sequence Analysis

miRNA Resources:

• MirBase
• free database of miRNA sequences
• TarBase
• free database of experimentally validated miRNA targets
• miRecords
• database of miRNA-target interactions
• IPA miRNA-target analysis
• commercial database that includes free databases as well as a proprietary list of miRNA-target interactions found using text-mining of the literature
• TargetScan
• free tool to predict miRNA targets
• sylArray
• tool to predict miRNA targets from gene expression data.  Uses gene ranking, so it doesn't require mRNA differential expression (although you will need to check that the miRNA regulator is differentially expressed)

In general, I think you really need both miRNA expression and mRNA expression data to get reliable results when trying to identify miRNA-target interactions

RNA-Seq Splicing Events:

• JunctionSeq - extends DEXSeq to include junction coverage (including junctions not defined among isoforms in reference database).  Strictly speaking, it only calls differential exon and junction coverage (and provides a statistic at the gene-level), but the junction coverage can be helpful in identifying some other types of splicing events.
• MATS - Provides differential splicing for skipped exon (SE), alternative 5' splice site (A5SS), alternative 3' splice site (A3SS), mutually exclusive exons (MXE), and retained intron (IR)
• MISO - Provides single-sample and differential splicing for skipped exon (SE), alternative 5' splice site (A5SS), alternative 3' splice site (A3SS), mutually exclusive exons (MXE), retained intron (IR), tandem 3' UTRs (TandemUTR), alternative first exon (AFE), and alternative last exon (ALE)

RNA Secondary Structure:

• Mfold
• RNAfold

RNA Domain Homology:

• Rfam
• may be helpful in predicting function of a non-coding RNA of unknown function

de novo Assembly Algorithms (RNA-Seq):

• Oases
• Trans-ABySS
• Trinity
• eXpress - mRNA quantification tool that works with both de novo assembly transcripts (as well as transcripts from direct genome alignment)

RNA-Seq QC

• FASTX-Toolkit - popular suite of tools to quantify and manipulate sequences .fastq and .fasta files
• samtools - popular suite of tools to quantify and reformat .sam/.bam files
• Picard - Java-based implementation of samtools; CollectRNASeqMetrics can produce a coverage plot (normalized per start to end of transcript)
• RSeQC - package to produce a variety of RNA-Seq QC figures

General RNA-Seq Analysis

• Wikipedia list of RNA-Seq bioinformatics tools
• Please see Gene Expression Analysis for tools for statistical analysis of RNA-Seq data