Round-up March 28th – April 3rd

I will be taking a month off from Round-ups — next install in early May.

In the next step of the CRISPR patent dance, the European Patent Office has announced its intent to grant the UC Berkeley crew a patent that would have broad coverage of CRISPR; though this will almost certainly be challenged.

Analysis of protein truncating variants from the ExAC group to identify which genes have the strongest selection against loss of function finds these have a strong overlap with genes known to be lethal in mouse knockouts.

A large scale joint analysis of Structural Variation and gene expression found that SVs are causal at 3.5–6.8% of expression quantitative trait loci (eQTLs) – a larger estimate than previously thought. Moreover, the effect size of SVs was larger than for SNVs or indels. Most of these SVs effected regulatory elements.

CiVIC is an open data project linking somatic mutations to particulae cancer types. Illumina has just announced that they will contribute over 8,000 associations to CiVIC, tripling the size of the database.

Variation linked to more production of the vitamin folate, and a higher BMI, have been found in Tibetan genomes, potential clues as to how they have evolved to thrive in an environment with 40% less oxygen than sea level.

Stanford researchers introduced Transcribed Genome Array (TGA), for probing transcriptome wide binding affinities using a hardware/software system based on the MiSeq.  “Our work couples transcriptome-wide measurements of binding affinity, sequence, and structural determinants of binding, and phenotypic outcomes to provide a comprehensive portrait of Vts [a developmental regulator] function.”

A win for the intersection of cognitive neuroscience and genetics, with the discovery that the expression of several genes is linked to brain activity during memory processing.

In some parts of the world, infection with the fungal aflatoxin causes 80% of liver cancers. A clear mutational signature of this infection has been reported, holding out promise for early detection and assessing exposure.

A GWAS of over 12,000 cases identified new risk loci of glioma suggest a polygenic susceptibility, and different signatures for glioblastomas and non-glioblastoma tumors.

5% of reading ability is attributable to genetics (compare 1% attributable to gender)

Repositive, a new service for aggregating genomic datasets.



Round-up March 21st – 27th

Last week was the American College of Medical Genetics’ annual conference. I’ve yet to find a good write up or summary anywhere!?

Where do cancer causing mutations come from? Traditionally, we have focused on inherited mutations, and environmentally caused mutations. But there is a third source, arising from errors in DNA replication. A study in science reports that this third source, which are unavoidable, are responsible for two thirds of mutations in cancer. This strong role for “bad luck” (rather than behavior) has previously caused controversy.

study in Nature uses the mutational signatures of cells of adults to elucidate facts about the very earliest stages of embryonic development. They report that each cell division results in three new mutations, and that the two daughter cells tend to contribute to cell numbers in a 2:1 ratio.

GSK and Regeneron have teamed up with the UK BioBank, to sequence the genomes of the 500,000 individuals who are part of the BioBank cohort, with 50,000 expected in 2017. The ten year old UK BioBank is a cohort of individuals with extensive health records, described as “the world’s most comprehensive health resource”.

The chromosomal level abnormalities underlying different types of acute myeloid leukemia (AML) have been known for a while; a large study correlates this with underlying mutational changes, allowing for subtyping the disease.

CAP and AMP publish guidelines for the validation and monitoring of NGS based somatic panels.

personal story about why it is so important that we do not allow GINA’s protections to be eroded, form a woman who speaks of “mutants like me”.

Making the case for the role of bioethicists in a healthy research environment.

As rounded-up last week, the results of the PSCK9 trial were generally perceived as underwhelming. But, Robert Plenge writes, as a proof of concept for genomic based medicine, the results were encouraging.

Variants that affect splicing have a good chance of being disease causing. Its often not possible to assess whether a variant affects splicing computationally; an experimental technique using a hybrid minigene based method.

study showing that recurrent pregnancy loss is associated with lower number of copy number variants in the placenta.

An information-theoretic approach to the epigenome.

variant in MAOA (one of the most controversial genes in the genome, sometimes called the warrior gene), already linked to alcoholism and smoking behavior, has been linked to heroin addiction.


Round-up March 14th-20th

The news this week has been dominated by Trump’s plans to cut the NIH budget by 20%. We’re also bracing for the coming storm of announcements/reported results expected from the American College of Medical Genetics conference, which starts in Phoenix, Arizona, tomorrow.

In the nature-nurture debate, twin studies have played a decisive role in helping tease apart the relative contributions of genetics and environment. A meta-analysis of twin studies covers ~18,000 traits and ~15 million pairs of twins, shows an average heritability of 49% across all traits.

Oxford Nanopore have announced the launch of a new desktop product, the GridION X5. It is five of its MinIONs plus a lot of compute in a box, and much smaller than the PromethION. Written up my Omics! Omics!.


  • A “good news” variant in PCSK9 is associated with lower levels of LDL cholesterol and lower chance of heart disease. A large scale clinical trial of a drug that targets PCSK9reported today that it did work, but not as much as analysts had been hoping for, and perhaps not enough to justify the $14,000 price tag.
  • More tumors than previously thoughtmay be BRCA1/BRCA2 deficient, meaning that more patients could potentially benefit from PARP inhibitors.
  • eGenesis, a spinout of George Church’s lab, has raised $38m in Series A financing. They aim to make pig organs transplantable into humans, using genetic modification to combat organ rejection.
  • A clinic in the UK has been the first to be given the go aheadto make three person babies. The UK recently made the procedure legal.
  • HudsonAlpha is offering an “elective genome”at $7000. 7 of the first 24 patients had actionable information reported. The focus is on rare disease, one only those genes associated to conditions that the patient has a personal or family history of. The test is in large part being offered because patients ask for it — but this isn’t necessarily good reason to offer a test.
  • A number of companies are trying to use DNA as a tracer molecule– an alternative to dyes or radioactive materials.
  • Making the case for building the infrastructure to report on protective variants.

New methods

  • Apaper showing that an antibiotic compound allows some cells to “read through” premature stop codons, giving hope to those who suffer from rare disease caused by such mutations.
  • A group has reported single cell level structural maps of the mammalian genome, at a resolution of less than 100kb. Some things are constant between cells (A and B compartments, lamina-associated domains and active enhancers and promoters), while some vary (individual topological-associated domains and loops).
  • Some tumors can be attacked by a combo of drugs that act synergistically. A CRISPR-based double knockout (CDKO) system, designed for high-throughput detection of which pairs of genes give a phenotype when knocked out, allowing synergistic drug target combinations to be identified. Another study of 142k gene-interaction testsreplicated combinatorial drugs at 75% precision.

New genetic associations


Round-up March 7th – 13th

Canada has passed a Genetic Nondiscrimination bill. Insurance groups opposed it. So did PM Justin Trudeau, saying it impinges on Provinces’ rights to regulate the insurance industry.

Meanwhile, a US House Committee approved a bill that will enable companies to inflict financial penalties on employees who do not submit to genetic tests, thus undermining GINA’s (Genetic Information Nondiscrimination Act) ability to protect the genetic data of employees. Employees who refuse testing for “workplace wellness” programs will face reduced pay, fines, or inflated insurance premiums. Tom Price, the HHS Secretary, has said there would be “significant concerns” about the bill, and that they’d be taking a look at it when it got to the department.

The Personalized Medicine Coalition has published a report on current opportunities/challenges.

On the opportunity:

  • Percentage of the patient population for which a particular drug in a class is ineffective, on average: ANTI-DEPRESSANTS 38%; SSRIs ASTHMA DRUGS 40%; DIABETES DRUGS 43%; ARTHRITIS DRUGS 50%; ALZHEIMER’S DRUGS 70%; CANCER DRUGS 75%
  • There are 132 personalized medicines on the market; ~42% of drugs in the development pipeline include biomarker investigation as part of R&D; personalized medicines accounted for 27 percent of new drug approvals in 2016

When it comes to challenges:

  • Lack of regulatory in landscape puts some investors off;
  • Reimbursement, where there is a Catch 22 situation “Widespread insurance coverage of diagnostic tests, for example, will likely require practice-based evidence demonstrating value. Obtaining the real-world data necessary for generating this evidence, however, is difficult unless the products and services in question are covered by insurance policies.”
  • Decreased payment rates, partly because the CMS moved from allowing “stacked codes” to a “gapfill” methodology, which allows regional contractors to set prices
  • A new rule that appeared in the Protecting Access to Medicare Act (PAMA) may put downward pressure on utilization of personalized medicine, as there is no mechanism for capturing the value of targeted treatment
  • Clinical Adoption is slow due to lack of education and lack of IT infrastructure — “most health care organizations do not have formalized plans to leverage advances in genomics and data analytics to personalize patient care, and are unprepared to implement personalized medicine programs”

Scott Gottlieb has been chosen by Trump to head the FDA. The most moderate of the names doing the gossip rounds, he is thought to support maintaining ensuring drugs are both safe and effective before approving them — some other candidates supported dropping the “effective” part.

Science news

  • An article in Naturereports on a new technique for uncovering the 3D architecture of the genome, including mulit-enhancer contacts.
  • Where do circulating DNA fragments come from? A new methodlooks at methylation haplotypes to determine tissue origin — allowing for cancer status and tissue origin to be determined from a blood draw. This could be a big deal in the liquid biopsy space. Singlera Genomics will attempt to commercialize the technology. Sensitivity can be increased by running another methylation test in parallel, based on the open/closed chromatin status.
  • The gene CDH2 has beenimplicated in sudden cardiac death.
  • The gene SEMA4D has beenlinked to obesity in African populations – those with variants in this gene were on average 6lbs heavier. Obesity is more common in those with African ancestry than others, and other populations lack variation in the gene. The study highlights how important it is to study disease associations outside of Caucasian populations.
  • A review on using genetics for transplants.
  • Alarge effort to sequence plants used in Chinese Medicine.
  • And on the subject of prediction, a model that incorporates omic-datato predict years of life post treatment for breast cancer is able to explain some of the variance after more conventional variables are factored in.

In the “healthy exome” space, Arivale have started offering polygenic profiles — i.e. giving their customers risk scores that aggregate over many variants. There is little data that speaks to the scientific validity of this.

George Church is teaming up with brain training game Lumosity to uncover the genetics behind those with outstanding memory.

Geisinger are leading the way with implementing genomic medicine. Here is a Mendelspod interview with their Director of Clinical Genomics.

There are dozens of direct to consumer tests that allow for determining paternity. This study looked at the privacy policies and terms of services of 43 such companies, and concludes that “recreational genetics carries both the risk of unintentionally revealing misidentified paternity, and also the risk that fathers will deliberately use these services to test their children’s paternity without revealing their intentions to the mother or any other third party.”


Round-up Feb 28th – March 6th


  • The first patient to have undergone a particular gene therapy for sickle cell disease has had his disease reversed, with no symptoms in 15 months. A huge success for a field that has struggled, his treatment involved removing his bone marrow, using a (non-CRISPR) gene therapy technique to remove the genetic variant responsible for the disease, and returning the bone marrow.


Germline news

  • Two large studies reporting on the genetics of autism
  • 5205 individuals from autism-effected families, identifying 61 autism risk genes, 18 novel. This is part of the MSSNG project, a joint Google-Autism speaks venture.
  • 686 autism patients sequenced using 10X’s platform for synthetic long read sequencing, one of the largest studies to probe structural variation at scale, revealing a diversity of complex structural variation
  • The American College of Obsteticians and Gynecologists has recommendedexpanded carrier screening for genetic disorders in all women during and before pregnancy.
  • Proove, who have $2m a month revenue test to combat opioid addiction based on genetic markers,  are under the spotlightfor a series of dodgy practices. Their story is being used as an example of why the FDA is right to think that it needs to regulate the genetic testing space.
  • February 28th was Rare Disease Day. To mark the occasion Stephen Kingsmore, he of the 26 hour Whole Genome based diagnosis of newborns, complains: “I think the one thing that I would like technology-wise is better software for going from genome sequence to diagnosis. Right now the software systems that we have are not quite good enough to be scaled up to meet the needs of all the children that we could benefit. There is still way too much manual effort involved.”
  • GenePeeks will let you know how your genome would combine with another — one step beyond carrier screening, the explicit intent is to help you select an egg or sperm donor. They just announced partnershipswith an egg donation agency and a surrogacy.
  • Data harmonizations remains a key challenge in germline analysis. The $280m Centers for Common Disease Genomics (CCDG) program, who aim to sequence and analyze the data of ~150-200,000 individuals in existing cohorts, have just announcedtheir standard sequence analysis pipeline.
  • Emory University School of Medicine and genetics/biobanking company Akesogen are partneringon a study of the genetics of diseases that hit later in life, aiming for 100,000 participants.
  • Noninvasive Prenatal Testing, where the genetics of the fetus is determined based on a sample of the pregnant mother’s blood, has attracted the attentionof the Nuffield Council for Bioethics, who are calling for a moratorium on using it clinically for whole genome sequencing. Currently, the test is only routinely used for detecting trisomies, but whole genome sequencing of the fetus is debatably already here.


Cancer news

  • It was a big week for fund raising in the noninvasive early cancer detection space, with Freenome raising $65m, and Grail $900m. Grail is using some of the money to repurchase some of Illumina’s stake.
  • Foundation Medicine reports dataon use of tumor mutation burden for predicting response to checkpoint inhibitor therapy. “In a cohort of 65 metastatic melanoma patients, the median TMB value was 37.9 mut/Mb in the responder group and 6.6 mut/Mb in the non-responder group.” Similar findings for NSCLC and bladder cancer have previously been reported. (The idea is the following: some cancers avoid the immune system via mutations that lead to over-expression of immune checkpoint proteins; in such cancers, drugs that inhibit/block the inhibitory checkpoint molecules work by “taking the breaks off” the immune system; cancerous cells with more mutations produce more immune-reactive neoantigens, i.e. peptides that the immune system recognizes as non-self; the immune system, when let loose, will be better at attacking and destroying these cells.)
  • Data sharing efforts for cancer genetics: The NCI’s Genomic Data Commonsaims to collect data from >50,000 cases by the end of 2017. Foundation Medicine have contributed data from 18,000 cases; this adds to AACR’s GENIE project, at > 18,000 publicly available samples as of January. Harmonization of data format is one of the key issues. The Global Alliance for Genomic Health sees itself playing the coordinating role across all of these efforts, via the proposed Cancer Gene Trust.
  • Actionable results are found for large numbers of cancer patients, but only a small fraction go on to have their treatment affected by those tests. GenomeWeb have a nice writeup, summarizing the pitfalls at each stage of the process.
  • Once upon a time, cancer’s in different parts of the body were studied separately. With the advent of molecular profiling, the role of pathways and particular driver genes lead to a more body-wide approach. A reviewfocusing attention on organ-specific tumorigenesis.


Other Research

  • The FANTOM project has been investigating long non-coding RNAs, and thinks there may be ~19,000 of them that are functional, and some of which already have evidence of disease association.
  • Linking genotype to other things happening in the cell…
  • “Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites” – a paper looking at genotypes and levels of 644 metabolites in 1960 adults
  • What significance GWAS hits? A high-throughput method to detect associations between protein levels and genetic variants (pQTLs). Move over eQTLs.


In Other News

  • Another milestonein using DNA as a storage medium. Some researchers encoded a bunch of files (including a film) using a method they call DNA fountain, sent the DNA across the country, where it was decoded with zero errors by another group.
  • By comparing a 45,000 year old wooly mammoth’s genome to a 4,300 year old specimen, researchsuggests that the last Wooly Mammoths (of which the second sample would be one) were so inbred (“low effective population size”) that their genomes were riddled with deleterious mutations, in work that could shed light on conservation efforts for still extant species.
  • Some local police departments in the US have created their own DNA databases, because getting results of a sample’s match to the state or national data base can take 18 months, and they can turn analysis around in under 1 month by outsourcing to private labs. This is proving controversial, for example with the ACLU filed a lawsuit against San Diego. The concern is that local authorities are side-stepping all the regulations put in place at the state and national levels to protect citizens from a surveillance state.


Round-up Feb 20th-27th

Do you remember when 1000 genomes sounded like a large number? The team that gave us ExAC released GnomAD in its full form today, which includes the exomes of 123,126 individuals and the genomes of a further 15,496 individuals.

And just in case that didn’t sound ambitious, this week the Earth BioGenome Project was announced, a plan with a name, an estimated $20b price tag and no funding to date, which aims to be a Noah’s ark of genomes: “the first step would be to sequence in great detail the DNA of a member of each eukaryotic family (about 9000 in all) to create reference genomes on par or better than the reference human genome. Next would come sequencing to a lesser degree a species from each of the 150,000 to 200,000 genera. Finally, EBP participants would get rough genomes of the 1.5 million remaining known eukaryotic species.”

My favorite read of the week is a STAT interview with Jeantine Lunshof, a bioethicist embedded in George Church’s group — a very unusual setup for a very unusual lab.

Meanwhile, in the somatic world:

  • NewGuidelines for “Molecular Biomarkers for the Evaluation of Colorectal Cancer” have been set. The 21 recommendations make it clear that NGS has a clear future in the treatment of this type of cancer.
  • The NCI-MATCH Trial, which aims to assess the effectiveness of molecular based treatment decision for cancer patients, has enrolled 4500 patients to date, 4000 who have had results returned. They reporta 18% match rate (lower than expected) to one of 24 treatment arms, with 72% of patients enrolling in the matched trials (higher than expected)
  • In an oncology sample, you have dozens of somatic variants, but only a small handful will be “drivers” (functional roles that confer cell fitness advantages), and the rest will be hangers along, or passengers. Which are the driver mutations? Many efforts have focused on molecular level properties, such as frequency and amino acid effect. Here’s an approachbased on patient outcomes.
  • new computational toolfrom UCSD for somatic samples, Haploinsufficient/Triplosensitive Gene (HAPTRIG), which focuses on single gene copy number losses/gains and how these may aggregate up to effect a cancer pathway, has demonstrated utility for Serous Ovarian cancer patients, and is expected to be useful for other cancer types.
  • Cynvenio, who offer ClearID, a test for late stage breast cancer patients, and Color, who offer a hereditary cancer screening test, have partneredto enable a low cost, high convenience option for oncologists.

23andMe and Celmatix are launching a 4,500 women project aimed at understanding factors underlying fertility

Korean start up 3billion is launching an exome DTC for rare disease patients at a TBD price tag less than $1000. They will be presenting “annotated rare disease variants along with published information about them”, and thus hope to avoid the ire of the FDA

In the world of bacteria:

  • studyreports that ribozomal mutations in bacteria cause resistance to a broad range of antibiotics.
  • A group trying to use CRISPR to fight bacterial resistance, this time with the “chainsaw” Cas3 as supposed to the “scissors” of Cas9.
  • studyon the use of an NGS test to detect meningitis and encephalitis is being run to assess both clinical utility and cost-effectiveness. The clinical pathway involved use of a clinical microbial sequencing board. The group, which is also developing a test for Lyme disease, is already looking at complementing the metagenomic DNA data with RNA expression data.

The wooly mammoth may be de-extinct soon, but do we want to go there?  “It’s better to spend the money on the living than the dead.” says one commentator, in reaction to a study that looks at whether de-extinction will be good for conservation efforts.

Most translation starts with an AUG. Before this week, we knew of a couple of other “non-canonical” start codons. But now, translation start has been shown from 47 of the 64 codons.


Round-up Feb 13th – 19th

What a week. On Tuesday, a report a year in the making said that germline genome modification should not be prohibited — an update on the previous position that it would be irresponsible to proceed without broad societal consensus. The story was picked up just about everywhere. I’ve been thinking about it for a couple of days, and have summarized my disagreement with the report here.

Then on Wednesday the CRISPR patent dispute went in favor of the Broad/MIT/Harvard rather than UC Berkeley/University of Vienna. The latter group were the first to show use of CRISPR as a genome editing technique in bacteria, and filed patents covering all cell types. But the Boston set were the first to show that it also worked in eukaryotic cells, and filed for this use. The California group claimed that these patents overlapped with their own, but the Patent Trial and Appeal Board judged that the Boston patents did not interfere: “because one of ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful in an eukaryotic environment”. Editas, which has an exclusive license to medical breakthroughs resulting from the patents in dispute, saw its stock jump by more than 30% on the news. Summaries from the Broad and from UC, the latter stating they are “pleased that its patent application covering the use of CRISPR-Cas9 gene editing technology for all cell types can now move closer to issuance”. That is, this is not over yet.

In other gene therapy related news, researchers have successfully made a mouse glow after injecting it with the mRNA of the same protein that makes fireflies glow. This type of gene therapy would be transient, and particularly suitable for vaccinations — current vaccines involve introducing viral material in order to get the bodies immune system to respond; this technology could potentially directly instruct the body to produce its own antigens. The key to the work was the development of a molecule that helps get mRNAs into cells.

High overall tumor mutational burden (TMB) is an indicator for response to immunotherapy, probably because more mutations means more neoantigens, means more targets for the immune system in combating the cancer. PGDx are developing a circulating tumor DNA test, targeted at regions in the genome that their previous exome sequencing work has indicated are good surrogates for overall TMB.

The move to pre-prints in biology is heating up, with ASAPBio launching its plan to become a centralized repository. The twittersphere reacted strongly, saying that we already have that with the bioRxiv.

There are dozens of genetic changes that have an impact on presence of genetic diseases. A group in Michigan published something that they think many of them have in common: they fall in regions where the transcription factor “Regulatory Factor X” is predicted to bind in islets, groups of cells in the pancreas that produce insulin.

In an article entitled “The next pseudoscience health craze is all about genetics“, Gizmodo argues, using very specific advice given out by DNA Lifestyle Coach as an example, that “lifestyle advice has a tendency to sound more like it was divined from a health-conscious oracle than from actual science”.

For clinical adoption of genetic tests, health providers want to see evidence it works. Startup Geneticure are launching an 800 person prospective randomized controlled trial of their pharmacogenomics test for hypertension drugs, hoping to show that their test enables patients to get to controlled blood pressure faster, with less medication.

Okay, this isn’t actually from this week, but I missed it, and its worth rounding-up. In October those involved in the Genome write project launched a white paper. “The Genome Project-write (GP-write) will use synthesis and genome editing technologies to understand, engineer and test living systems.” Its main goal is to drive technology development, and particularly to lower the cost of writing genomes. A sub goal is to “understand the functional properties and phenotypic consequences” of the human genome. Possible pilot projects mentioned include:

  • Making cancer resistant human organs in vitro
  • Making human cell lines able to produce vitamins and all amino acids (which humans, unlike some bacteria, have not evolved the ability to do)
  • Transforming the pig genome to make it “far more amenable” for human organ transplantation
  • Making an “ultrasafe” human cell line (its worth checking out what properties they’re aiming for on p14, includes virus resistant, radiation resistant, cancer resistant, to name but a few)

They want to launch the project with over $100m pledged, and have a tentative roadmap. A proportion of funding should go to ethical, social and legal issues raised: “We encourage public discourse to occur surrounding HGP-write, and that having these conversations well in advance of deliverables will help society better prepare for and guide emerging capabilities.”

A  paper, summarized with implications by GenomeWeb, illustrates just how widespread the problem of DNA damage is, induced for example by library prep. They find evidence for DNA Damage in the 1000 genomes data, for example. They come up with a score to quantify the amount of damage in a sample. A computational approach can be taken to reduce the effect of these errors: “One way to deal with damaged-induced sequencing errors is to filter out affected reads, which can be flagged because the G to T mutations occur only in one read direction but not the other.”

A great success story from the Cincinnati Children’s Cancer and Blood Diseases Institute, who report on the successful use of sequencing for patients with histiocytic disorders, with impacted clinical outcomes.

In other research news: The Oxford MinION is sensitive enough to pick up methylation patternsCoffee consumption is associated with DNA methylation levels of human blood; evidence that “Untimely expression of gametogenic genes” can cause uniparental disomy (UPD) — UPD in humans usually leads tocongenital disease; some replicated, exome wide significant associations to bipolar disorder, including rare coding variants for the first time; genetics of self-reported tiredness.