Round-up Sept 30th – Nov 9th

The annual American Society of Human Genetics conference happened in October in Orlando, ensuring that there was plenty of research news. The N of some studies is truly outstanding, with >10,000 seeming normal. Meanwhile, self-CRISPRing has definitely started, the role of multiple driver mutations in a given tumor is increasingly clear, and an eclectic mix of stories make it into a section I decided to call Social Backdrop”.
A moment to stop and reflect that October 24th marked the 20th anniversary of the screening of GATTACA. This is a film that I have seen raised by genetics professionals several times in the context of concern about the future we are headed to. 
Genetic modification
Social backdrop

Catch-up July 31st – Sept 29th

I have once again fallen behind in Rounding Up the news, so here play catch up, over what has been a very busy two months.
Genome editing
  • In a world first, a Chinese group have used a technique called base-editing to cure a genetic disease in a human embryos. Whereas CRISPR cuts DNA, base editing directly changes the base, leaving the DNA strand intact. The paper is from the same group that published the first CIRSPRing of human embryos. 
  • A survey of Americans found that about two thirds were generally accepting of genome editing for therapeutic purposes. About a third were supportive of genome editing for enhancement reasons.
  • First in human gene therapy trial in the US started, using Zing fingers to target Hemophilia A. Meanwhile, Reuters reports that the two gene therapies approved in Europe have seen sales of only 3
  • The scientist who edited the first human embryo in the US stresses that the main result of his work was that the embryo did not incorporate the supplied healthy” DNA, but instead preferentially incorporated an extra copy of the mother’s DNA. This puts the prospect of designed babies further off.
  • Following news of germline human genome modification, several genetic professional societies published a joint statement on the future of the technology, covering the following positions: (1) At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy. (2) Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research. (3) Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input.”
  • A version of CRISPR that acts on RNA, with potential clinical applications e.g. to Huntingtons.
  • CRISPRcon, help in Berkeley in August, was designed to pull people to talk about a world with genome editing.
  • A great quiz from the New York Times for seeing how up to the times you are on genetic engineering. Contains reference to several of the recent major stories. 
  • Meanwhile the Onion tackles the pros and cons of genome editing. 
  • And a nice summary from Ed Yong of what the recent human embryo editing means and doesn’t mean.
And on making babies
  • Some men are infertile because they have XXY or XYY sex chromosomes. Scientists have demonstrated a technique in mice where they create sperm from ear cells via stem cells, loosing one of the extra chromosomes along the way.  
  • On that note, a review of where we’re at with infertility technology, with a particular focus on making artificial gametes.
  • The FDA has sent a cease and desist letter to the NYC based doctor who was offering mitochondrial transfer to couples (so called three person babies, legal in the UK).

Round-up July 18th – 30th

Reports of the first genetic modification of embryos in the US by scientist Shoukhrat Mitalipov, who previously created the first cloned monkeys and has cloned human embryos via cloning. The as yet un-published work applied CRISPR at the point of fertilization, thus “getting in early”, and presumably avoiding mosaicism. Previous modification of human embryos was reported by Chinese teams. At one stage it looked like a moratorium would be issued for human germline modification in the US, but a NASAM report in February of this year stopped short of that. My take on that report is here. Although clinical applications of such research would not be legal in the US, the research paves a way to a genetically modified future for humanity.

In other big genetic modification news, CRISPR has been used to restore muscle function for mice with Muscular Dystrophy. Whereas most approached to date rely on homology-directed repair, this study uses nonhomologous end-joining.

The next round of the CRISPR patent battle commences, with an appeal led by UC Berkeley against their East Coast rivals, led by the Broad. The UC group unquestionably first demonstrated use of CRISPR for genome editing. But the Boston group first applied the technique to eukaryotic cells. The California group’s case turns on their argument that this use was obvious.

Meanwhile, the FDA is one step closer to approving the first ever gene therapy.

Helix have launched their app store for your genome”. For an initial $80, costumers will have their exome sequenced. They will then be able to buy Apps on the Helix store, each of which will plug in to a bit of this data and return information to the customer. The idea is that customers will come back again and again. Geneticist Daniel MacArthur has concerns: “Promoting tests with little or no scientific backing runs the risk of inflating customer expectations and ultimately undermining consumer confidence in genuinely clinically useful genetic tests,” Another geneticist, Stephen Montgomery, has launched a satirical take on direct-to-consumer genetic tests, which then went viral.

MRSA, methicillin-resistant Staphylococcus aureus, has long been supposed to have evolved following the widespread adoption of methicilin in clinical practice. But new research suggests that MRSA evolved before the adoption of methicilin, and the resistance instead evolved in response to penicillin and other first generation drugs.

A key combination immunotherapy trial failed, stoking criticisms that this approach ahs been over-hyped.

A biotech executive and cancer patient on resetting expectations about cancer treatments: “I think everybody thinks cancer’s just about to be cured, when we have a little bit more work to do… I think if we can pop that bubble or at least reset people to have dialed down expectations for some of these breakthroughs make that in the public’s best interest.”

A bill that continues to allow the FDA to charge pharma companies to review their products must be passed by Congress, but is being held up by a Senator who wants to insert a “Right to Try” clause as an amendment. A medical ethicist argues why the inclusion of a right to try” clause would undermine clinical trials.

Why are dogs more friendly than wolves? The canine equivalent of a region associated with Williams-Beuren syndrome in humans — a condition marked by hypersocialability amongst other things — has been found to be under positive selection in domestic dogs.


Round-up July 10th-17th

The first CAR-T therapy, this one for Leukemia, is one step closer to approval after an FDA advising committee gave it a unanimous thumbs up.  The therapy takes out a patient’s T-cells, modifies them to express Chimeric Antigen Receptors (that are good at recognizing tumor cells), and injects them back in.

A new German center that will sequence 1000 genomes a year in an aim to capture species biodiversity.

A controversial genetic test for gum disease has been withdrawn. The test had been drawing criticism for many years as overselling the clinical utility of genetic testing in this area, and is given as an example of why the FDA needs to wade in to regulate lab developed tests.

Trace Genomics will analyze which bacteria are present in soil to give input to farmer’s making planting decisions.

Doudna’s group publishes on the discovery of an “anti-CRISPR DNA mimic” that can reduce the off-target effects of CRISPR-Cas9.

A study using CRISPR in a ScanDel approach — tiling 1-2kb deletions, to see which regions near a gene were essential for its expression.

Public outreach shouldn’t just mean convincing the public that we know best. Biotechnologist Esvelt has plans to do R&D in a radically open way.

Verily (parent company, Alphabet) are releasing millions of mosquitos infected with a bacteria to make them sterile, in an effort to combat zika.

A study claims that ~75% of the genome is junk”, where junk means something like not under selective pressure. This is in stark contrast to ENCODE, which claims there is evidence for ~80% of the genome to be functional. The new study seems to claim that for a site to be function, a rare variant would make the individual non-viable.

Its been known that epigenetic effects can be inherited for quite some time, but its now been shown that inherited epigenetic modifications effect gene expression.


Round-up May 31st – July 9th

I have slipped in my resolution for a weekly round-up. Here is another catch-up. And there has certainly been a lot to catch up on!

Germline news

In the first ever randomized controlled trial of whole genome sequencing for healthy adults, which reported on variation across genes linked to Mendelian disease, many participants were found to have variants believed to definitively cause disease by adulthood, even though they were living disease free. STAT has a write-up.

At one point, it was thought that diseases such as obesity, or traits such as height might be polygenic in nature, i.e. affected by variation in some set of closely involved genes. Genome Wide Association Studies are premised on this idea. But it is challenged by a recent paper that puts forward the case for the omnigenic model i.e. almost every gene effects every trait, because of how interconnected the networks are. If true, this suggests that we should be concentrating on mapping out the networks operating in different cell types. Ed Yong has a good write-up.

Veritas has launched myBabyGenome in China. For $1500 parents can find out about a series of traits (e.g. how novelty seeking” their child may be) and disease risks. But as genetics prof Jim Evans says You run the risk of predestination based on bad science”. They won’t be told about e.g. variation that leads to an increased risk if Alzheimers. Instead, they will be offered the chance to purchase that information later on.

A study of families in Scotland involving 20,000 individuals reports that brainier people have fewer variants that impair general health and intelligence, rather than possessing variants that make them smarter. While twin studies suggest that 50-80% of intelligence is based on genetics, studies to date had been able to attribute only about 30% of the variance to genetics the gap is known as the mystery of missing heritability”. This study was able to explain this gap, because it could isolate the effect of very rare variants usually too rare to be missed, but because of their presence in families, detectable by this study. The results are support for the mutational load” paradigm for thinking of genetic endowment.

Huntington’s sufferers have one normal and one altered copy of the gene HTT. A study that used CRISPR-Cas9 to knock out both copies of HTT in mice found no negative effects and improvements in symptoms.

Over 1000 new reference genomes of bacteria and archaea have been deposited by the JGI.

New York fertility doctor, Dr Zhang, who evaded US regulations and went to Mexico to oversee use of the three-person baby technique, has started a company to market this technique. It will market not only to couples wishing to avoid passing on mitochondrial disease, but also for age-related issues.

A study that looked at the combination of pre-implantation genetic diagnosis (PGD, performed for Mendelian diseases such as Cystic Fibrosis) and screening (PGS, performed to test for aneuploidies such as Downs), found that the combination resulted in more pregnancies given embryo transfers, but fewer transfers, as for more couples no viable embryos remained. After PGD, 56% of embryos were deemed transferable. After PGS, only 27.5% of blastocysts were deemed transferable. Standardly, about 34% of transfers result in pregnancies. Following both PGD and PGS in this study, the number was 49%.

How much of heritability comes from common (>5% frequency) variants? A new study suggests about 43%.

Why hasn’t natural selection reduced the amount of coronary heart disease? This study provides novel evidence that CAD has been maintained in modern humans as a by-product of the fitness advantages those genes provide early in human lifecycles” paper here

Analysis of mummy DNA suggests Ancient Egyptians individuals were more similar to present day people from the Near East than to populations residing in Egypt today

The Precision Medicine Initiative, launched in 2015, has just started beta enrollment in its All Of Us program, which aims to be a 1 million strong cohort. 

Age-related somatic mutations have typically been of interest because of cancer. But they are also of potential relevance for other disease types. A large-scale study finds that a particular type of somatic change in blood cells doubles the risk of coronary heart disease. Which is a good segway into…


Somatic related news

Encouraging results from a small cancer-vaccine study: 6 melanoma patients given a cancer vacine unique to their tumor saw no recurrence. The technique works by first sequencing the tumor, to work out which sections of the DNA make antigens that the immune system is most likely to respond to, and that are different from germline cells. Next, millions of copies of each of 13-20 of these neoantigen regions are injected.  The idea is that the patient’s immune system learns to recognize these sequences as other”, and will then target the cancerous cells.

Evidence that PARP inhibitors perform better than chemotherapy for women with metastatic breast cancer who also have germline BRCA mutations. There are three PARP inhibitors approved for ovarian cancer on the market.

A study of a regulatory region that is well conserved between humans and mice finds when this region is deleted a) mice develop normally, and b) mice are resistant to tumor development, making it a promising drug target. 

Following Keytruda’s approval based on a bimarker indication across all cancer types, new FDA commissioner Gottleib has promised more guidance to allow more drugs to follow this path. 

Flatiron and Foundation have shown the utility of their joint molecular-clinical dataset, including the demonstration that those with an actionable variant have a survival time of 35 months, compared to 19 months for those without.

 A nice synopsis of oncologists’ thinking about genetic testing, arising out of ASCO.

Merck paused two studies of Keytruda in combination with other therapies for multiple myeloma, because of unexplained deaths.

Accurate software for distinguishing germline variants from a tumor without the need for a matched normal sample.

Round-up May 22nd-30th

A study published today showing CRISPR off-target effects knocked CRISPR stocks, despite the fact that the findings were old news. 

The FDA have approved the first therapy based on molecular feature rather than tissue of origin. About 4% of all advanced cancers have the genetic characteristics involved. Merck won the apporval based on an accelerated” process, off the back of a trial of 149 patients.

The Broad have released the latest version of their genome analysis software, GATK, under an open source license. The software, which has 45,000 users, was previously costly for non-academic use.

A meta-analysis of the genetics behind intelligence identifies several genetic loci that collectively explain 4.8% of the variance in intelligence. An editorial in Nature argues that we have historical reasons to fear the field of intelligence studies (history of racism, history of eugenics, fears of biological determinism), but we shouldn’t this hold us back from showing that there is no genetic basis for discrimination”.

When it comes to complex disease, GWAS have historically found relatively common variants of small effect. Larger sample sizes are a way to go, as is using isolated populations in the hope of identifying founder mutations, as this study does to uncover a variant protective against heart disease.

How rare is rare enough for a variant to be possibly causative of disease? This all important cut-off affects how many variants must be considered when evaluating a case. The paper from the ExAC group that lays out a framework for defining this cut-off is finally out, though of course it was up on BioRxiv months ago, and was previously rounded-up here.

Nature reports that police in Xinjiang, China, have been collecting blood samples and are building up DNA sequencing facilities that go beyond what would be needed for regular forensics. There is no clear framework for legal use of the data.

NPR reports on CRISPR use outside the lab. 

Catch-up! April 4th – May 21st

I’ve moved jobs and had a month traveling since my last round-up. An attempt to capture the most significant happenings over the intervening few weeks below, before resuming my regular weekly schedule.
I am now working for Driver, with a mission to cure cancer, so expect to see an increased emphasis on all things somatic.
Having been blocked from reporting health results for a few years, 23andMe are now allowed to report on 10 diseases direct to consumer, with no physician in the loop. The list does not include tests whose results cold affect treatment decisions (e.g. BRCA1/2)
  • the ACMG are opposed
  • those that they’re at higher risk for Alzheimers are over 6 times as likely to purchase long-term care insurance. Individuals are supposed to share such information with their potential insurer (unlike for health insurance), but the industry fears people won’t (New York Times).
  • on the average, individuals do have measurable lifestyle improvements, and 25% credit their genetic results (improvements were not associated with any particular genetic result). This is in contrast to previous studies, which found no improvement
More than two thirds of ~100 oncologists said they would prescribe immunotherapy rather than a targeted molecular therapy, because the shot of a durable response from the former outweighs the fact that resistant genotypes will be positively selected for in the latter. This follows on from a survey reporting 70% of 132 oncologists said genomic testing was below expectations’.
Two studies on 100 non small-cell lung cancer (NSCLC) cancer patients (the TRACERx study):
  • Samples from many regions finds elevated CNV heterogeneity associated with shorter survival (NEJM
  • Using the tumor sequencing results, the team designed an individualized multiplex-PCR test for each patient, and use the results to show they can predict patient responses/outcomes in some cases (Nature). They also find predictors of which patients have more circulating tumor DNA.
MSK have reported that their IMPACT test for cancer patients identifies clinically relevant mutations for 37% of patients. 11% of patients enrolled on a clinical trial as a result of a variant found. They are optimistic about predicting response to immunotherapy boosting these numbers further (Study N=5009, currently about 17,000 patients).
A study of 100,000 cancers has found that tumor mutational burden (TMB) can be assessed accurately from just ~1.1 Mb of sequence, and report recurrent promoter mutations in PMS2 associated to high TMB.
A study in Nature of the whole genomes of different types of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and reports that most cancers had actionable mutations.
Noninvasive prenatal screening (NIPS) started with chromosomal abnormalities (now reccomended for all pregnancies), and has more recently been extended to the smaller scale microdeletions. Now Natera say they are developing a noninvasive prenatal screening test that will cover  de novo mutations in 30 genes, which will cover diseases that collectively cover diseases found in 1 in 600 births. 
Broad researchers introduced Sherlock via a Science paper: it uses Cas13a, a CRISPR associated protein that targets RNA rather than DNA, as part of a very sensitive molecular diagnostic to detect e.g. strains of Zika, with potential point of care applications
Canada passed an anti-genetic discrimination law that went into effect on May 4, which means no-one can be required to have a genetic test or disclose the results of a genetic test, but PM Trudeau is challenging its constitutionality
Experimental evidence of long-lasting (14 generations) epigenetic memory of environmental change in C elegans

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