Round-up August 1st – 22nd

Thermo apparently made a $30bn offer for Illumina, though neither party has commented on the speculations, and analysts argue it would make no sense for either party:

The ExAC paper is out,, and something more accessible from STAT: I already covered some of the results of this >60,000 exomes analysis when the article appeared in preprint, but its important enough to recap:

  • Each ExAC subject has ~54 variants classified as causing a genetic disorder, almost all of which are false positives. i.e. ExAC highlights how bad existing databases are — because of their reliance of studies of very small sample size
  • 99% have a frequency of <1%; 54% are singletons (variants seen only once in the data set); 72% are absent from both 1000G and ESP data sets
  • It covers: one variant for every 8 base pairs (bp) within the exome intervals; 7.5% of all possible synonymous variants; 63.1% of possible CpG transitions (C to T variants, in which the adjacent base is G); 3% of possible transversions; 9.2% of other possible transitions
  • 72% of LoF-intolerant genes have not yet been assigned a human disease phenotype despite clear evidence for extreme selective constraint
  • Filtering on the highest allele frequency in any one population (‘popmax’) rather than the average (‘global’) allele frequency was best for identifying pathogenic variants
  • “The abundance of rare functional variation in many disease genes in ExAC is a reminder that such variants should not be assumed to be causal or highly penetrant without careful segregation or case-control analysis”
  • Average individual has 85 heterozygous and 35 homozygous protein truncating variants (PTVs), only ~2 singletons
  • “discovery of homozygous PTVs is markedly enhanced in the South Asian samples, which come primarily from a Pakistani cohort with 38.3% of individuals self-reporting as having closely related parents, emphasizing the extreme value of consanguineous cohorts for human knockout discovery”

Related stories

  • Many variants previously reported pathogenic are now considered benign, particularly as the result of large scale analyses that show some of these variants are fairly frequent in the population. This misclassification has particularly affected those of African descent, a study on cardiac variants reports. This is largely because of the lack of individuals of African descent in large scale population databases.
  • A study of mutational rates across cardiac genes makes the case for domain by domain knowledge in variant interpretation, and points to much misclassification in databases:
  • In a paper entitled “Using Genetic Technologies To Reduce, Rather Than Widen, Health Disparities”, a group of academics make the case for policy to ensure non-hispanic whites do not get the majority of the benefits from genomics:


Quest/Athena have replied to Amy William’s in the latest step in this genetic-testing drama. Recap: Athena, now owned by Quest, reported a mutation in the plaintiff’s son, Christian, as a Variant of Uncertain Significance. The variant is now reported as pathogenic for Dravet syndrome, a diagnosis which, if made at the time, would have altered Christian’s course of treatment and possibly saved his life (he died age 2). The report, issued in 2007, was sent to Christian’s clinical geneticist, with the recommendation that the parents be tested to assess whether or not the variant was de novo. Ms Williams says she never saw the report. Quest/Athena have asked for the case to be dismissed, and that decision is pending. “If allowed to go forward, legal experts believe that Williams v Quest/Athena could define what constitutes the standard of care for a genetic testing lab.”

Oxford Nanopore and Illumina have reached a settlement over the latter’s suing of the former. The case settled on a particular protein pore, which is not used in the latest ONT product anyway:

Foundation Medicine has submitted its FoundationOne product to parallel review by the FDA and CMS: “If approved, FoundationOne could be the first FDA-approved comprehensive genomic profiling assay to incorporate multiple companion diagnostics to support precision medicine in oncology, including an indication for use as a companion diagnostic across a diverse range of solid tumors.”

A documentary about the Undiagnosed ( has spawned a consortium dedicated to extending genomic analysis of six undiagnosed individuals to contextual info beyond the genome. The participants (in academe and industry) met on the 16th August to assess their results, though the rest of us may have to wait until the film airs in early 2017 to hear how they did. This endeavor is a follow on from the CLARITY challenge.

George Church’s lab is nearing completion of an E-coli genome engineered to use a different genetic code – one that eliminates 7 ‘redundant’ codons, thus freeing them up for potential reuse:

A systematic review of the potential integration of WES into clinical care found interpretation of variants of unknown significance, incidental findings, and the cost and reimbursement of WES-based tests as the most commonly reported challenges.

A blog article making the case for the relevance of genomics to public health (from the Director of the Office of Public Health Genomics, Centers for Disease Control and Prevention):

Blood forming stem cells have been extracted from patients with sickle cell disease, and modified using CRISPR to produce high (and healthy) levels of foetal haemoglobin:

Some cancer-treatment combos work better if the tumor has a higher mutational load:

The Human Functional Genomes Project, which aims to large-scale map genetic variation to functional consequence, has published data on 500 individuals related to immune response, and has more similar projects in the pipeline:

Weaver, a new graph based variant caller from U of Illinois, focused on somatic samples and structural variation.

The UK’s project to do WES or WGS pre-natally, after abnormal ultrasound, is starting to return results to clinical teams:

Counsyl have made the scientific case for expanded carrier screening over existing guidelines (which are more targeted). Their business model rests on such screening.

Google are continuing their push into genomics, with a big partnership with Stanford Health announced:

Oxford Nanopore have announced they can now do direct sequencing of RNA:

How did life on earth begin? Before the modern relationship between DNA and RNA, the “RNA world” hypothesis is that RNA acted both as storer of information and as cellular catalyst. That story just garnered extra weight by the creation of an RNA molecule that can make copies from other RNA molecules (it can’t copy itself, thats a hope of future research). The study used in vitro evolution.

New study of bacterial evolution shows that most new persisted mutations are beneficial:


Round-up, July 12th – 31st

Research highlights

Type 2 Diabetes is known to have a strong genetic component. GWAS analyses have found several associated, relatively common variants (>5% frequency). A huge study looking at WES, low coverage WGS, and SNP data has found very little else. There had been the hope of finding “synthetic association”, i.e. the idea that common GWAS SNP signals come from nearby rare causal variants in linkage disequilibrium. But they found very limited evidence for the role of rare variants in Type 2 Diabetes. An accessible write-up: The original paper:

Money from the ice bucket challenge has helped find some genetic underpinnings to ALS, otherwise known as Motor Neuron disease, and with Steven Hawking being a patient. Two papers:, and NYT write-up:

Circulating tumor DNA is ~20bp shorter than other circulating DNA, which may help the sensitivity of assays:

A new reference genome for the Qatari population (called QTRG), which produces ~750,000 fewer variants compared to the standard reference:

In genetics we have the notion of heritability — how much of a trait is due to genetics, as supposed to environment. For most traits, the amount of heritability we can explain is lower than the estimates of heritability from e.g. twin studies, leading to the notion of “missing heritability” — to be hunted for in NGS data. A new study suggests there may be less missing heritability to be found, because estimates of overall heritability have tended to be inflated, as common elements in environments have not been taken into account:

Some standardized terms for clinical reporting of pharmacogenomic variants have been proposed by an international consortium, in the hope that this will help ease PGx data into clinical care. Table :

A review on the promise of re-evaluating WES data over time

Market News

Cornell have the first NY State DoH approved somatic exome test. They present their computational framework, and claim that in 82% of cases they found something actionable. They play up their abilities to capture structural variants and recently characterized variants as compared to hotspot panel testing. They have an in house knowledge base for assessing actionability:

Software called OncoTrack quantifies the amount of DNA per gene (SPKMG, Sequence Per Kilobase of exon, per Megabase of the mappable Genome), aimed at CNV and LOH analyses. The measure is proposed to be helpful for looking for phenotype associations, and for tracking a cancer over time. It operates on BAM files.

Pathway Emerge will be using the software of GenomOncology, who have a solution for labs reporting out on molecular tests (NGS, FISH, karyotyping, RT-PCR, IHC, and others):

Sanford Medicine will be using Translational Medicine’s software for reporting, initial focus on pharmacogenomics:

N-of-One, who provide curated info on somatic variants, raised a $7m Series B

LabCorp are purchasing Sequenom, who produce non-invasive prenatal tests, for $302m.

Phosphorous, a new computational genomics company, has raised $10m Series A. They have a test for predicting cardiac risk, and a test for familial hypercholesterolemia, with plans for more. They aim to be the “hub of a new computational biology network”:

Commentary and Context

James Watson is not impressed by the cancer moonshot, calling it “crap”, and “the same old people with the same old ideas”:

The ACMG have said non-invasive prenatal screening can replace conventional testing for trisomies 21, 18, and 13 in most women:

Carl Zimmer is keeping on with his “Game of Genomes”: season 1 here,, season 2 here,

The WSJ on healthy people and genome sequencing, giving pilot results from the PeopleSeq project, investigating healthy human attitudes to genome sequencing, e.g. reasons given. Predictably one of the comments is the one word “GATTACA”:


Round-up May 23rd – July 11th


I’ve been away for a while, so a higher level catch-up below.


The FDA has introduced two new sets of guideline docs for NGS testing

1) how test developers could demonstrate the analytical validity of NGS tests for germline diseases

2) guidance on how they might establish the clinical validity of genetic variants gauged by such tests using public databases recognized by the agency

The reaction has not, in general, been positive, e.g.. ‘”They don’t know what they’re saying,” she said, adding that test developers already have good guidelines from CAP and NYSDOH. “What does the FDA think it’s going to add to this?” posited Bale, who is a founding member of the American College of Medical Genetics and Genomics, and an author on NGS standards issued by the group in 2013. “From a technical aspect, they are way in over their heads.”‘

The FDA are trying to distant these guidelines from their proposal to regulate Laboratory Developed Tests, but they’re not convincing many.

The French have launched a national $780m genomes project (cf $215 for the US’s Precision Medicine Initiative), “The first objective is to make France a leader among the countries already laying the groundwork for genomic medicine. Second, is to prepare for the integration of genomic medicine into the normal course of patient care in the country, which means sequencing about 235,000 genomes per year by 2020. And the third goal is to establish a national genomic medicine industry to serve as a source of innovation and economic growth.”

The NIH has a new data system for sharing of genomic data, including clinical data, and focused on cancer data:


“CMS Preliminary pricing plan would reduce payments for several molecular tests“:

InsideDNA will launch in the Fall a Google cloud service that allows users to plug and play various different bioinformatics tools, for e.g. variant calling, but also discovery tools:

Genos, a consumer genomics company arising out of the ashes of Complete Genomics, will give consumers a VCF of their exome, and put them in touch with genetic counsellors if requested. They will make their money by allowing researchers to ask users if they can pay to access their genetic data.

Illumina is looking to make big bucks of software, including variant interpretation:

IBM have partnered with the DVA, with Watson to recommend treatment options based on genetic analysis of veteran’s tumors:

Counsyl move into Oncology with a new business unit:

IDbyDNA, out of Mark Yandell’s lab, is still in stealth mode, but it is based on an exclusive license to the Taxonomer software, details of which were recently published. Taxonomer is a metagenomics tool to identify which pathogens are present.

Hortonworks, who focus on open and connected data platforms, is leading a Big Data/Spark/Hadoop open data consortium, involving Baylor, Mayo, and others:


The LawSeq project has been launched, which will look at: liability, quality of data and variant interpretation, privacy, and frameworks for research-clinical translation.

A study of consumer attitudes to WGS found a lot of heterogeneity, including that 38% of people would not pay for anything for actionable variants, 7% would pay more than $400, and that 3% would pay more than $1000.

Genomics helps enable precision medicine, but its also relevant in public health. The CDC has launched this new database on the relevance of genomics to public health, which will be updated at least weekly:

Scientists behind the “Human Genome Project – Write” published on some of their pilot project goals, and the overall vision:

Mount Sinai reports on using WES and RNA-Seq for tumor-normal analysis

A GenomeWeb write-up from some of the results presented at ASCO includes the report that Foundation’s panel test can be used to assess overall Tumor Mutational Burden. Some studies suggest that high TMB can give better response to therapy.

Craig Venter reports on deep sequencing of 10,000 genomes. One nugget: each genome contributes about ~8,500 novel variants.

A score based on several SNPs helps predict the age at which you start reading, which in turn predicts some socioeconomic outcomes: The score only helps predict ~2% of the variance, but will surely be an early example of whats to come…

A pilot study of 20 sick babies at CHEO identified genetic causes in 40% of them using the TruSightOne panel.

A three year Uganda based study will look for genetic markers that dictate TB and HIV progression in children across three countries:


Round-up, May 10th – May 22nd

George Church is back in the news, this time for the plan to write a human genome within the next 10 years:

In January, the Department of Health and Human Services updated  what data can be requested by patients about themselves, to cover most things: This was published on a blog and went somewhat unnoticed, but has just come into the limelight as several individuals asked Myriad for all their genetic variants (including benign variants). Myriad initially said No, and although complied after they became aware of the new regulations, the plaintiffs have not dropped their HIPAA complaint. The individuals wanted the benign variants so that they could upload them to ClinVar. Science’s write-up is a must read:

The White House is targeting Mircobiomes for a bold new funding push, with an emphasis on going beyond findings correlations to building tools to get at causation:

The US Equal Employment Opportunity Commission (EEOC) just updated regulations that the ASHG argues means that “employees who decide to keep their own and their spouses’ health information private may have to pay “significantly higher health insurance premiums” than those who share their information”; “”The new EEOC rules mean that Americans could be forced to choose between access to affordable healthcare and keeping their health information private”:

A fascinating read about the relationship between study designers, their participants, the journalists who report on them, and the public reaction:

Natera are finding they are starting to see good reimbursement for average risk pregnancies for their Non-invasive prenatal screening test:

UK start-up PetaGene has a business model based on compressing sequence files, so their customers spend less on storage:

A GenomeWeb interview with the head of BGI Research, focusing on Clinical Tests. One of their projects is a cloud based computer  platform, “we are not just going to offer kits and instruments but also software in the future”:

Happy 10th birthday, Next Generation Sequencing! A review:

A study that looked at concordance between WES and Sanger found the big issue for WES remains poor coverage of certain areas, for which Sanger is still needed — 42 of 51 genes analyzed had “adequate” coverage (over 75% of sequence with coverage of greater than 20×), and for these concordance was very high (97.3%, with not all discrepancies due to WES data):

A study of various labs variant classification using the AMCG/AMP guidelines found high discordance, but that the criteria gave a good framework for talking about differences. The paper does a good job at illustrating how the criteria are being interpreted, including when they are being altered:

A big data-mining project representing joint work from the New York Genomes Center and 23-and-Me has found many variants involved in multiple traits, and some pairs of variants linked causally:

Illumina’s MiSeq does not do well with the sequence ‘CCCGCC’:

A platform to aggregate patient level clinical trail data, Vivli, is gathering steam:

An overview of several studies show human evolution at work: On the shortest of time scales, selection in the middle of the 20th century for an allele that makes it harder to quit smoking has been shown in the UK population.

A method proposed to replace the need to find controls for matched case-control studies, using publicly available data — the concept is termed the Universal Control Repository Network (UNICORN):

Various studies of cancer outcomes from patients who underwent somatic genetic testing have shown less than stellar results, but often on small sample sizes. A meta-analysis of 13,000 patients has shown clear benefit:

The NIH is funding four new studies on the ethical, social, legal implications of genomics:


Round up April 24th – May 9th

Astra-Zeneca are co-ordinating the sequencing of 2m genomes, with multiple partners, including Venter’s HLI, the Sanger, and Genomics England:

Geisinger Health System are sequencing 100,000 exomes (to be expanded to 250,000) – this is an interesting read on a healthcare systems’ genomics ambitions. One advantage they have is the ability to recontact patients to help resolve VUSs:

Foundation Medicine launched a liquid biopsy test, for those cancer patients for whom a tumor sample is unobtainable.

NantHealth is filing for an IPO

The National Human Genome Research Institute will spend $21.8M to assess the cost effectiveness and clinical utility of sequencing

A study that did WGS on 560 breast cancer tumor samples concludes that “the genes harbouring the substantial majority of driver mutations are now known” — there’s about 90 of them. They also identify “genetic signatures” of the cancer– “Each mutational process will leave its own specific pattern on the genome or mutational signature”. A consequence of this is that “statistical models involving mutability cannot assume uniform genomic mutation rates and must consider signature dependent variation as a factor in all future analyses”. BBC write-up: Driver genes:, Signatures:

Memorial Sloan Kettering have announced some of the effects of their MSK-IMPACT tumor-normal panel. They now report on germline variants, and about 20% of patients have pathogenic hereditary cancer variants. Data on the proportion of patients with clinically relevant information returned is not available, except for lung cancer, where it is ~77%.

An overview of hereditary cancer risk, as provided by the American Society of Clinical Oncology for their oncologist members:

Before the ACMG guidelines were published, the International Agency for Research on Cancer (IARC) had a probabilistic framework for interpreting VUSs. A paper that used the two alongside each other found only “slight agreement” between the two methods:

ClinGen have developed a framework for the actionability of disease-gene pairs, and have published the results of applying this framework to the 56 incidental finding genes (see Table 3):

A description from AstraZeneca on how they define actionability in somatic samples that are part of early stage clinical trails:

De novo assembly of a human genome without long reads? 10X and BioNano have joined forces to produce a high quality such assembly based on Ilumina tech:

An easy read on Oxford Nanopore’s technology,, and a more scholarly take on the history of nanopore sequencing:

A Huffington Post blog on the current relevance of genetic testing on mental disorders argues that we are nowhere near ready for prime time: Another blog on personalised medicine in cancer states we are only pursuing this in cancer because ““you are selling hope in a bottle, and you cannot refuse people who are dying”:

The beautiful story of how Thailand have implemented a simple wallet card for the results of a pharmacogenomics test, for which 8% of their population will test positive. The card indicates whether the patient will succumb to an often fatal disease if given a particular drug.

A study that shows that ethnically based Genetic Risk Scores (using aggregates of individual variant effects to predict disease risk) do better than non-ethnically based ones:

A study using ENCODE data to try and elucidate function of intergenic SNPs that are associated with disease: Another study that looks at the combined effects of SNPs on disease risk, focused on Coronary Artery Disease

A review on modeling propensity for common diseases, including environmental factors:

Two alleles associated with having twins have been discovered via GWAS, with large effect sizes:

And finally, how do your genes influence your politics?


Round-up April 4th – April 23rd

Veritas Genomics are offering a $999 genome, ordered through your genome, with results accessible via an App. You can see the list of conditions and traits that they will report on here.

Astra-Zeneca are partnering with Venter’s HLI (which recently raised $220M in venture funding) to analyze 2 million WGS, in a 10 year, $100ms deal.

Kaiser have announced a sequencing initiative for 500,000 of their members, with the aim of drawing actionable information into their members’ EHRs

AncestryDNA have received an undisclosed amount of funding, and are being quiet about what the money will be used for

Wellderly Case-Control analysis published: Wellderly are those with the healthy-aging phenotype, the “disease-free aging in humans without medical interventions.” The cohort of 511 “Wellderly” have a significantly lower genetic risk for Alzheimer disease and coronary artery disease, but no difference for diabetes or cancer risk. One of the first examples of WGS case-control looking at both rare and common variants.

Across nearly 600,000 individuals, 13 were found that should have died from disease — so called genetic superheros. Following up with these 13 is impossible because of how they were consented, and Daniel MacArthur uses this to make a call for “a willingness of participants to donate their genomic and clinical data, and a commitment by researchers and regulators to overcome the daunting obstacles to data sharing on a global scale.”

New development for gene-editing: “the new technique basically means that CRISPR just went from handling DNA like a meat cleaver — to handling it like a scalpel”

A second Chinese group have published the results of using CRISPR on (non-viable) human embryos, attempting to knock out the CCR5 gene, a mutation known to protect against HIV. 4 of the 26 embryos were successfully edited.

AMP has published cost analysis of WGS. Labs reported costs of

  • five to 50 genes for solid tumor samples: $578 to $908.
  • tumor panel with greater than 50 genes: $1,948.
  • hearing loss sequencing analysis: $1,048 and $1,949.
  • exome sequencing: $1,499 to $3,388.

The article also performs a cost-benefit analysis of WGS, with all scenarios they test coming out on the benefit side.

The Broad Institute, who maintains the most frequently used variant-calling pipeline, GATK, is launching GATK in the cloud, across all the main providers.

Envision, a spin-out company from Hudson-Alpha, are offering WGS in a clinical setting for $6500. They claim analysis times of 1-1.5 hours, based on their software, Codi. The group has been controversial in its advocacy of WGS rather than WES. They say the number of variants that end up being analyzed are almost identical for exomes versus genomes, but some diagnoses are possible with WGS and not in WES.

Pharmacogenomics Clinical Annotation Tool (PharmCAT), is being developed as part of a consortia. It will annotate a VCF with all CPIC level-A variants, to be published under Creative Commons

DNAFit, a company that will give you tailored training advice based on your genetics for $140, has published a study claiming that there test makes a difference to performance

A nice write up of the decisions couples face when considering pre-implantation genetic diagnosis, from Genome Magazine

GWAS hits for “subjective well-being”, and for cognitive function

Hypo-methylation at the MAOA locus has been linked to panic disorders. New research shows that those patients who undergo successful Cognitive Behavioral Therapy have their methylation patterns returned to more normal levels

Round-up March 17th – April 3rd

A review from some GSK scientists arguing for integrating genetic based drug-efficacy into clinical trails, despite the fact that at GSK they have done 17 such GWAS and not found anything clinically actionable. They argue that “only a minority of truly efficacious drugs are likely to have clinically meaningful genetic predictors of efficacy”

The European Society of Human Genetics has published some musings on expanded carrier screening, which also serves as a useful survey of carrier screening

  • “Since the stated aim of reproductive screening (including carrier screening) here is not prevention, but rather the provision of options for reproductive decision making, appropriate pre-test information and voluntary decision making becomes an essential requirement rather than a mere side-constraint: without this, the screening cannot fulfil its aim.”
  • Success of programs should be judged on whether “informed choice and reproductive decision making” is optimized (not by birth prevalence of affected children)
  • They suggest that the risk of information overload may limit the type of tests that should be performed.
  • Consent as one of the most challenging issues, and the possibility of “generic consent” should be explored

Some more commentary on the Athena case, highlighting the risk that cases such as this could prevent the fledgling genetic testing field from  really getting off the ground:

Sequenom’s patent for non-invasive prenatal testing has been struck down, with lower courts citing the influence of the Supreme Court’s “sweeping language” in the Mayo v Prometheus. This case struck down a patent for a personalized medicine based approach to setting drug dosage level,_Inc. Sequenom will now. appeal to the Supreme Court:

23andMe will be launching “Genotyping Services for Research” in Q2, whereby they will genotype and provide 23andMe accounts to participants in trials. Engaging those involved with research trails is seen as a challenge for many studies, and this is an easy way to give something back to them.

Qiagen have teamed up with Intel to offer a complete highly-scalable genetic testing pipeline, announcing analysis of a whole genome for $22. Note: “analysis” means variant calling:

Craig Venter has made a bacteria with 473 genes, which is considered an “MVP” of a genome. 149 of these genes have no known function (though are essential).

A programming language for DNA:

Some analysis of PacBio’s threat to Illumina:

Risks in the genetic testing industry, a summary of a set of interviews with genetics professionals. Main risks linked to lack of physician education and pace of technology development:

A study using the 150k participants in the UK BioBank have quantified the lifespan reduction of having certain SNPs:

Large GWAS meta-analysis of the genetics of cannabis use finds no significant SNPs, but four genes:

On secondary findings, and how not to over interpret them:

The case continues to grow that the genetic code may be more flexible than we think, with extra codons shown to code for selenocysteine, the 21st amino acid (i.e. just outside the canonical set of 20):

Making the case for individuals owning their health data, and the risk of the “unpatient”: