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”: