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.

 

Some thoughts on the recommendation to “proceed with caution” on human germline modification

On Tuesday, a report a year in the making on human genome editing was released, prompting media coverage from just about everywhere. Whereas this report’s predecessor said it would be “irresponsible to proceed” with clinical human germline modification without “broad societal consensus, this update recommends against a prohibition.

In this post, I discuss how they couch this recommendation. Ultimately, I don’t think they offer any convincing arguments for the shift in attitude. While the debate is still hypothetical (there are ongoing scientific issues; the practice is currently illegal in the US), this report does have the ability to “change the tone” on the use of the technology, and it has seized that opportunity.

Overall Recommendations

Published by the National Academy of Science and the National Academy of Medicine, the report follows on from the International Summit on Human Gene Editing, convened in December 2015. The broad purpose of the efforts are to respond to the rapid technological advancement of genome-editing tools (particularly CRISPR-Cas9): to consider their potential medical uses, and the ethical, social and legal issues that arise.

For all research applications, the authors contend that existing ethical norms and regulatory frameworks will work just fine1.

Recommendations for clinical applications are organised under two main distinctions: Somatic (non-heritable) versus Germline (heritable), and Therapy versus Enhancement. The recommendations:

Therapy Enhancement
Somatic (non-heritable) Existing ethical norms and regulatory regimes satisfactory2 Do not proceed at this time; engage with the public
Germline (heritable) Approach with caution, but do not prohibit; ensure stringent oversight system3


It was the failure to recommend an outright ban on germline modification that caused some surprise. As Francis Collins, Director of the NIH, noted in 2015, the “concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed”. And as the authors state in the report: “Given how long modifying the germline has been at the center of debates about moral boundaries, as well as the pluralism of values in society, it would be surprising if everyone were to agree with this recommendation.”

In addition to putting frameworks in place to ensure due consideration of health and safety concerns, the authors want to ensure

  • there are no “reasonable alternatives”
  • societal benefits and risks are balanced, and that the public should be involved in this process
  • the principle of transnational cooperation is adhered to
  • there are “reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition”

I expand on these considerations below. I also look at the strategies for public engagement they propose.

When would there be no “reasonable alternative” to germline genome modification?

In brief, prenatal genetic diagnosis (PGD) – which is routinely offered as part of an IVF cycle –  would almost always be a reasonable alternative to germline modification, because selection of embryos will suffice to prevent the birth of individuals with severe genetic disease. Hank Greely makes this case in his book “The End of Sex”. There is one exception involving the incredibly rare case of co-dominance.4

The authors give two other potential scenarios under which there would be no reasonable alternative to germline genome modification. One is that PGD involves “discarding affected embryos, which some find unacceptable”. This is hard to take seriously. Germline modification would also involve an IVF cycle, and not all embryos that get produced in a cycle are implanted, PGD or no. In other words, it seems hard to imagine someone who would be okay with the use of germline editing, but not with the use of PGD.

The authors argue that germline genomic modification could also be the only option as it could increase the number of viable embryos available for implantation — lack of viable embryos is a common failure mode for IVF cycles, and PGD reduces this number yet further. This seems to me to be a more reasonable consideration. However, this would assume the technology was perfect, and that prospects on the horizon such as using stem cells to make egg cells do not materialize.

All of this of course assumes that being something other than the biological parent of a child is not a “reasonable alternative”.

Balancing societal benefits and risks and involving the public

This report explicitly aimed to continue the dialogue initiated by an earlier effort, which concluded in December 2015 that it would be “irresponsible to proceed” with clinical human germline modification without “broad societal consensus”. This report, in contrast, calls for “continued reassessment of both health and societal benefits and risks, with broad on-going participation and input by the public” – a significant watering down of the importance of public opinion and attitudes to impact on society.

Embracing their own methodology of a risk-benefit analysis (which is far from the only take), how do the benefits and risks of the use of germline genomic modification stack up?

Benefits the report mentions are:

  • Enabling prospective parents to have biological children free from serious disease (assuming no other alternative). It could be argued that this is a fundamental right in need of protection. “The number of people… might be small, but the concerns of people facing these difficult choices are real.”
  • The creation of a more level playing field for those whose traits put their children at a disadvantage
  • Public health benefits (though note these same benefits prompted the eugenics abuses of the past)

Potential risks mentioned fall under several themes:

  • Inability to prevent inappropriate or abusive applications
  • Recurrence of the abusive forms of eugenics practiced in the past
  • Further stigmatization of disability
  • Exacerbation of social inequalities
  • Creation of social pressure for people to use technologies they would not otherwise choose
  • Children being seen as “constructed products”
  • Parents increasingly viewed as responsible for the qualities of their offspring

The authors note that whereas most of the benefits accrue to individuals and are more immediate in nature, the risks mostly relate to society and are more diffuse. Because of this, arguments for the benefits and risks “can fail to engage each other directly.” That the benefits are more immediate can end up shaping how the risks are perceived: new technologies cause cultural change, partially mediated by the fact that individual decisions change societal norms. Regulations are based on cultural views, and, as the authors themselves note “it is the underlying change in cultural views that is precisely the slippery slope”. In other words, although the risks seem more diffuse, unless we give them due weight now, the sands will have shifted with early application of the technology, and we may find ourselves committed to a particular type of future.

Marcy Darnovsky, executive director of the Center for Genetics and Society, states that although the report does acknowledge the risks, “Strangely, there’s no apparent connection between those dire risks and the recommendation to move ahead.”I would agree that while the report is clearly written, it is often unclear how the recommendations arise out of the considerations raised.

Even if one agreed with the recommendation to “proceed with caution”, it still seems at odds with the very strong emphasis on the importance of public engagement throughout the report. Edward Lanphier, chairman of the DNA editing company Sangamo Therapeutics argues: “It changes the tone to an affirmative position in the absence of the broad public debate this report calls for.”Another example of the report not coming across as entirely internally consistent.

Transnational cooperation

Science and technology are transnational pursuits, but how we chose to apply them to our societies is necessarily contextual: “It is important to note that such concepts as “reasonable alternatives” and “serious disease or condition” embedded in these criteria are necessarily vague. Different societies will interpret these concepts in the context of their diverse historical, cultural, and social characteristics, taking into account input from their publics and their relevant regulatory authorities.”

The authors simultaneously call both for respect of cultural differences, and the promotion of regulatory standards. The latter is necessary to prevent medical tourism.The authors conclude their chapter on Germline modification with the observation that the current US legislation that prohibits the practice serves “to drive development of this technology to other jurisdictions, some regulated and others not.” It is unclear how much this consideration motivates the recommendation to “proceed with caution”. Bioethicist George Annas finds this position unconvincing: “the fact that something could be done even if outlawed is hardly a [reason] not to outlaw it if you think it should not be done.”8

I very much appreciated that the report actually gave some examples of cultural attitudes that could influence perspectives on genomic modification. We are familiar with the fear of “Playing God” from the Christian tradition. In contrast the authors note that: “In the Jewish tradition, on the other hand, there is an explicit obligation to build and develop the world in any way that is beneficial to people, and such improvements are viewed as a positive collaboration between God and humans, not as an interference with creation. Similarly, many Muslims and Buddhists view genetic engineering as just one of many welcome interventions to reduce suffering from disease”.

What of the distinction between Curing Disease and Enhancement?

The report does a good job of illustrating just how hard it is to draw the line between curing disease and enhancement, including:

  • What should be considered “natural” or “normal”?
  • What of preventative, rather than curative, measures (e.g. reducing chances of developing a disease or contracting an infection)?
  • What counts as a disease (homosexuality used to)?  
  • What about late onset diseases?

At the very least, we need some concept of a “problematic enhancement” – perhaps one that “confers a social advantage beyond that which an individual possesses by fate or through personal effort, and that does not benefit the rest of society in any way or undermines the implicit goals of a competition.”

The authors state that: “Of course, somatic or germline genome editing for enhancement is very unlikely to be the most profound source of inequality in any setting.”

In the US off-label drug use is generally permitted. The authors give one example, of genomic modification for muscular dystrophy being of interest to those who wish to become even stronger. They go on to state that “other examples are more difficult to envision” – something that may well turn out to be a failure of imagination.

Given the above, how “reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition” could be envisioned is left by the report authors as an exercise for the reader.

There is another option for public policy that the authors note – work to make advantageous enhancements broadly available.

Strategies for Engaging the Public

The authors state that: “A robust public discussion about the values to be placed on the benefits and risks of heritable germline editing is needed now so that these values can be incorporated as appropriate into the risk/benefit assessments that will precede any decision about whether to authorize clinical trials.”

Two of the main components in the approval of clinical trials are Institutional Review Boards (IRBs) and the FDA, and neither considers societal implications: IRBs are explicitly forbidden from doing so, and the FDA has no statutory mandate to consider public views.

There is a committee that considers public opinion and societal impact, the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC). It publishes non-binding guidelines. It does have public review, intended “to enhance public awareness of and build public trust in such research, allowing for a public voice in the review of the research”. Which sounds suspiciously like “educate the public about what’s good for them”.

The report argues that we will need more formalized efforts than are currently in place to enable the robust discussion called for, and that federal agencies “would need to consider” funding such efforts. Although they do go into detail about what this public engagement could look like, this call to action could have been considerably stronger.  

Conclusions

I would summarize the landscape thus. There are 1 in a millionpeople that cannot have biological children free of serious disease unless use of this technology is approved. Once this technology is developed for this use case, the technological barriers to applying it in other use cases, including for enhancement, will be low. The societal barriers will also likely be lowered. There is a concern of a slippery slope to applications that challenge our current societal values. There is also the possibility that other jurisdictions will authorize this technology. We need to involve the public in this discussion now.

On the report itself: It is very comprehensive and covers a lot of ground in a thoughtful manner; Perhaps inevitably given that it was written by 20 people, it is not always clear how the issues raised are aggregated into the overall recommendations.

  • The excitement around CRISPR-Cas9 and germline modification has eclipsed the fact that the cases in which it would bring benefit over preimplantation genetic diagnosis are few
  • The “proceed with caution” recommendation for germline modification is at odds with an insistence on public debate
  • I come away from the report further convinced that a slippery slope from curing severe disease to enhancement is inevitable

For these reasons, I do not support the shift in tone from prohibition to “proceed with caution”. Additionally, an opportunity has been missed to make a more actionable call to promote public discourse, particularly around funding of this research.

The report, at 150 pages long plus appendices, not a short read, but it is very accessible, and gives digestible overview both of the current state of the science and of several of the bioethical themes. Recommended reading!

 

Footnotes

1 In the US, there is a bar on federal funding being used in any research that involves destroying human embryos. In other countries, such as the UK and Sweden, there are no such bars and research is ongoing.

2 My co-author Sarah Polcz and I have argued that there are issues in somatic application worthy of particular attention, for example consent issues for minors.

3 Note that due to a budgetary provision in effect until at least April 2017, the FDA cannot consider clinical trials involving germline genetic modification, making the practice illegal.

4 The reasons that PGD suffices in almost all cases comes from basic principles of inheritance of genetic conditions: the fact that you get two copies of every gene, one from Mum and one from Dad, means that for dominant diseases (where one bad copy leads to disease), you make sure not to select the one in two embryos that have that one copy, and for recessive disease (where you need a bad copy of both genes) when both parents have one bad copy, you just make sure to not select the one in four that inherits both bad copies. There is one scenario that PGD would not work for: one of the parents has a dominant disorder, but actually has TWO bad copies of the gene. In this case, no embryos would be free from disease. Such “co-dominance” is exceptionally rare.

5 Quoted in an article in the Washington Post

6 Quoted in an article in Science

7 I can’t help but mention that in the utopia of the Star Trek universe, the Federation bans genetic modification for all except the correction of severe genetic disease. However, as Dr Bashir’s parents knew, there were some planets on the outer reaches of Federation territory where you could go to improve your genetics…

8 Quoted in an article in STAT

9 I made this number up based on an incredibly generous estimate of how many individuals with co-dominant alleles for severe diseases there are

Round-up Feb 6th – Feb 12th

When is a variant too common to be pathogenic? >5% is a hard cut-off according to the ACMG variant interpretation guidelines, but a frequency “greater then expected for the disorder” is also strong evidence for a benign interpretation, and a rate of 0,01% is suggested by this recent paper, provided that known founder mutations are taken into account.

This paper reports on core promoter strength across the human genome.

Most association work between genotype and phenotype is done on a variant by variant level. This paper reports on a haplotype based correlation between essential hypertension and a particular haplotype occurring with a particular haplotype.

DNA methylation patterns from single cells is here.

study that reiterates the importance of understanding the dosage pathogenicity of genes in interpreting the consequences of copy number variants.

Genomic medicine is constantly evolving. Who has the responsibility to ensure patients who have had genetic testing are kept up to date? A UK group recommends that re-contacting preferences be built into the initial consult.

The genetic underpinnings of the third largest cause of death in the US, ,Chronic obstructive pulmonary disease (COPD), are being uncovered.

When it comes to BRCA testing, a large majority of women who are at risk are not being recommended testing by their doctors.

How to separate the effects of genotype and phenotype? Subjecting those with identical genotype (identical twins) to very different environments (one in space, one not) can yield interesting results, and not just for those planning colonialization of Mars. The telomeres of the DNA of an identical twin sent to the International Space Station ended up longer than this stay at home twin.

Tom Price is the new leader of the Department of Health and Human Services. An advocate for the repeal of Obamacare, and an opponent of Medicare, will be sure to shake things up.

 

Round up Jan 30th – Feb 5th

After a couple of months off, I am restarting the weekly round-up with the aim of truly being weekly — Monday nights to be precise. Welcome back.

Let’s face it – this week it has been nigh on impossible to focus on anything other than the new administration. There have been some genomics related happenings:

  • Berkeley geneticist Michael Eisen has announced he is running for the senate, likely as an independent, because the new administration’s attitude of “basic rejection of the fundamental principles upon which science is based”
  • Trump announcedto pharma execs that his main focus for the FDA will be on improving time to market through decreased regulation. This has many in biotech concerned that hard won consumer protections may be lost, and that startups will not be able to compete alongside the pharma giants. Trump’s pick for the top job at the agency should be announced soon.
  • Meanwhile, although Biotech executives were quick to condemn the immigration ban, pharma execs were mostly quiet— perhaps because Trump thinks they’re “getting away with murder” on pricing, and are hence not wanting to rock the boot.

Despite being dropped by Roche last year, PacBio claims to be doing well. They improved the chemistry to the point at which de novo assemblies (i.e. with no reference genome) became feasible on their Sequel machines. Meanwhile BGI has announced that 2017 will be the year that the tech it bought from Complete Genomics really starts delivering. They will first deliver quantitative RNA-seq on their BGISEQ-500, with plans later in the year to deliver a $600 whole genome.

The MedSeq project, who performed WGS on 100 healthy people and 100 cardiomyopathy patients, has reported that 6 months after sequencing, those who had received WGS results has not cost their health care systems much more than those who had not. This is one of the very few studies providing data on the cost and benefits of WES/WGS. A major worry that payors have is that NGS testing will spark a flurry of expensive follow on tests.

Heidi Rehm weighs in on how low cost sequencing will impact health care. The usual emphasis on the importance of data sharing and models to encourage that. This sentence was thought provoking, “Although genetic counsellors will undoubtedly be critical in this space, it will also become increasingly important to facilitate knowledge-building through online tools and for individuals to take an active role in educating themselves about genetics.” What shape should these online tools take, who should build them, and how to encourage people to take an active role in educating themselves?

Over the last couple of weeks there have been a couple of events to show how seriously gene editing is being taken:

  • The ACMG published a Statement on Jan 26th 2017: “Genome editing is an area of very rapid technological change, so what is not possible today could well become a reality in the very near future… The potential for rapid advance of this approach, and the pressure to apply it clinically, should not be underestimated. The ACMG Board of Directors strongly encourages broad public debate regarding the clinical application of genomic editing.”  They also call out application to nondisease traits.
  • The FDA publishedits intent to regulate genetically modified animals in the same way they do drugs. This has not been popular.

 

Science – mostly association studies

Height has high heritability — 60-80% of variance in height is accounted for by genetics. We are moving from the world of genetic association studies that could only investigate common variants to the ability to probe rarer variants throughout the genome. When it comes to height, the work of the Genetic Investigation of Anthropometric Traits (GIANT) Consortium spans these approaches

  • In the first iteration of work in 2014, GIANT had focused on polymorphisms — variants that are common (>5%) in the population. They found 700 such variants associated with height, the effect size for any given variant was ~1mm. This work lead to ~20% of heritability of height being explained.
  • In their just publishedsecond iteration, GIANT focused on rarer variants (<5%, >0.01%) in protein coding genes, and found 83 variants, some of which contributed >2cm (nearly 1 inch) if height. Rarer variants like this are harder to study because you need larger sample sizes (this study used >700,000 people), but the rewards pay off. Now ~27% of heritability of height is explained.

This approach still used a chip design (rather than NGS). Explaining more of the heritability will come from larger sample sizes on the one hand, and looking at more of the genome on the other.

Meanwhile, a Chinese team has reported the first general population genome wide significant SNPs associated with mathematical ability, using a chip based assay to get at variants down to 2% frequency. Four SNPs in the SPOCK1 gene each effect match scores by 2.33-2.43 points. (The name of the gene seems very apt, though the high-functioning Vulcan was not the inspiration for the name). The motivation for getting at the genetic underpinnings of intelligence according to the authors: “Understanding mathematics ability is an essential step to improve children’s numeracy skills and academic achievements and could also provide novel insights into human brain functions.” This study is one of many in China focused on the genetic underpinnings of intelligence, something we in the West have far more “hang-ups” about studying.

Another large association study was published this week, this one on the genetic underpinnings of blood pressure. Part of the UK BioBank, this study used an exome chip (for variants down to 0.01%) as well as a SNP array (for variants down to 1%) and looked at over >140,000 individuals.

study of 1463 whole genomes from Finnish individuals compared to the same number of British individuals reveals some of the hallmarks of population bottlenecks, including more loss of function variants in the Finnish population.

The Dana-Farber Cancer Institute reports on their experience of WES for cancer patients, looking at both germline and somatic variants. “The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach.”

CIViC, a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer, has published a summary of their efforts to date: there are 1,678 clinically relevant curated interpretations of 713 variants affecting 283 genes, using 1,077 publications, and performed by 58 curators. They are dedicated to openness (cough cough HGMD).

Move aside genomics: a review of blood-based proteomics in setting cancer treatment

Round-up Sept 30th – Nov 8th

It has been too long since the last round-up, so here is a birds eye view of some of the more eye catching developments.

  • ASHG 2016 happened
  • The 4th Global Alliance for Genomics and Health happened
  • CMS has updated CPT codes, which is relatively good news for reimbursement potential of NGS tests.
  • Illumina and PacBio shares fall on Q3 earnings reports
  • PacBio suing Oxford Nanapore
  • When genetic testing goes wrong – the misdiagnosis of a family of 20

I am going to try to shift to weekly updates as of now!

ASHG 2016, some of my highlights (which you would have seen if you’d been following me on Twitter…):

  • Daniel MacArthur announces Genome Aggregation Database, contains 120k+ exomes and 15k+ genomes, gnomAD. Wow. #ASHG16
  • gnomAD, initial focus on analysis of protein-truncating regions; pilot studies involving recontact of individuals with “extreme genotypes” #ASHG16
  • Your age written in your genome – age predicted mean error 11 years from NGS data, using telomere length and mosaic chromosome loss. #ASHG16
  • Method to integrate 10k+ functional genomics datasets, can predict about half of conserved non-exonic bases #ASHG16

Global Alliance for Genomics and Health, 4th Plenary Session, some of my highlights:

  • The guiding principle of data sharing not protection from harm, but activating the right to benefit from science (UDHR 27) – B Knoppers @ #GA4GH2016
  • Improving care of individuals and families through “share, compare, resolve” framework for variant curation, BRCA Exchange #GA4GH2016
  • Match Maker Exchange as “a dating service for lonely exomes”, a federated network of databases for finding similar patients #GA4GH2016
  • We should call out those not sharing data, and be on the watch for those “sharewashing”. Voices of industry at #GA4GH2016
  • Data Working group mantra “collaborate on interface; compete on implementation”; data schema and API now available #GA4GH2016
  • #GA4GH2016incoming head Ewan Birney says we have to raise our game, got to make stuff that works practically, will bribe volunteers with chocolate

 

Market news:

CMS has upped the reimbursement for certain CPT codes covering NGS tests, though not enough for some: https://www.genomeweb.com/molecular-diagnostics/medicare-bumps-final-pricing-certain-ngs-tests-and-maaas-not-enough-some-say

On Oct 11th Illumina announced lower than expected Q3 earnings, driven by a “larger than anticipated year-over-year decline in high-throughput sequencing instruments”. Shares fell by 25% and have not recovered since. https://www.genomeweb.com/sequencing/illuminas-q3-revenues-fall-short-guidance-shares-tumble

PacBio’s shares also fell on its Q3 financial reports, despite revenue jumping 80%. It has launched a patent battle with Oxford Nanapore, seeking to ban ONT’s presence in the US: https://www.genomeweb.com/sequencing/pacbios-q3-revenue-jumps-80-percent-files-complaint-against-oxford-nanopore

PierianDX bought Tute Genomics. Pierian had been focusing its efforts on software in daignostic somatic testing, and Tute was primarily focused on germline. https://www.genomeweb.com/informatics/pieriandx-buys-tute-genomics-improve-clinical-informatics-workflow-constitutional

23andMe have abandoned NGS testing, instead focusing on their chip technology – NGS was too complex and the consumer price point not achievable. https://www.buzzfeed.com/stephaniemlee/23andme-anne-wojcicki-next-generation-sequencing

Veritas, who have a $999 genome on the market, have raised a $30m Series B: https://www.genomeweb.com/sequencing/veritas-genetics-raises-30m-series-b-financing-round

Illumina have launched a new 170 gene panel that uses a hybrid capture technique for DNA and RNA simultaneously. First only for research use, Illumina anticipate its use as a companion diagnostic by pharma companies: https://www.genomeweb.com/sequencing/illumina-expects-pharma-firms-leverage-new-tumor-profiling-panel-companion-dx

Invitae will offer the ACMG Incidental Findings 56 gene panel on the Helix platform: https://www.genomeweb.com/molecular-diagnostics/invitae-helix-bring-medical-genetic-testing-broader-market-through-apps

The UK government has made NIPT for trisomies 13, 18 and 21 standard of care. Although abortions are expected to rise, this number will be smaller than the number of miscarriages prevented because the use of amnios will go down: https://www.theguardian.com/society/2016/nov/04/new-prenatal-test-for-downs-syndrome-will-not-lead-to-more-terminations-nipt

You can now order a genomics test on Amazon: https://www.genomeweb.com/molecular-diagnostics/good-start-genetics-selling-carrier-screening-tests-through-amazon

Science:

HLI have published the results of deep sequencing of 10,000 individuals. They find that 84% of human genome can be reliably sequenced via Illumina technology. Each individual contributes ~8,500 novel variants. http://www.prnewswire.com/news-releases/researchers-from-human-longevity-inc-publish-paper-detailing-results-of-deep-sequencing-of-10545-human-genomes-300338937.html

Using Complete Genomics long reads technology, researchers at the Personal Genomes Project have published 100 haplotyped genomes, with associated phenotype data: http://gigascience.biomedcentral.com/articles/10.1186/s13742-016-0148-z

A study from Ambry makes the case for the continued need for Sanger confirmation, because achieving a satisfactory Specificity/Sensitivity for clinical applications with NGS is impossible, particularly in certain regions. They argue that training pipelines to assess variants in these regions is impossible except with vast validation sets, which labs are unlikely to be able to do. https://www.genomeweb.com/sequencing/ambry-genetics-study-indicates-continued-need-sanger-confirmation-ngs-testing

The BabySeq project, which aims to sequence both healthy and sick newborns, is having surprisingly low uptake, even in the sick baby cohort: http://www.sciencemag.org/news/2016/10/surprisingly-few-new-parents-enlist-study-have-baby-s-genome-sequenced

CRISPR potential for sickle cell disease. “What we have right now, if we can scale it up and make sure it works well, is already enough to form the basis of a clinical trial to cure sickle cell disease with gene editing,” first author Mark DeWitt told the LA Times.: http://stm.sciencemag.org/content/8/360/360ra134

A survey of the practices of clinical diagnostic labs finds large discrepancies particularly in “use of phenotypic data to inform case analysis and interpretation and reporting of case-specific quality metrics and methods”: http://www.nature.com/gim/journal/vaop/ncurrent/full/gim2016152a.html

An accessible discussion of the graph based genome. https://www.statnews.com/2016/10/07/dna-genome-sequencing-new-maps/:

— The first open access graph of ~1000 people will be available by the end of the year

— Seven Bridges unveiled a beta proprietary graph earlier this year – the NCI and the VA are both down to use it

— A competition is being set up by the Global Alliance to “find out who has got the best graph”

— Suspicion of proprietary tools and patents in the space

— Likes of MacArthur (of ExAC fame) thinks long term it will be a thing, but not in a hurry to make the transition away from tried and tested reference based tools

Also in the news:

A family of 20 was mis-diagnosed with a cardiac issue, with at least one very invasive procedure carried out. “When the pursuit of the genotype gets in front of the establishment of the phenotype, bad things happen.” http://www.frontlinegenomics.com/news/8153/family-study-wrong-genetic-diagnoses/http://www.sciencedirect.com/science/article/pii/S0025619616304633

There are over a dozen companies doing DTC genetic analysis of sports performance. This article is from a woman who ordered several of them and was very unimpressed by both the lack of concordance between tests, and the type of data that she received: https://www.statnews.com/2016/11/02/genetic-testing-sports/

J Lo will star in a new NBC series based in a world where CRISPR’s use is rampant: http://www.hollywoodreporter.com/live-feed/jennifer-lopez-sets-futuristic-bio-939509

 

Round-up August 23rd – September 29th

 

Highlights

Europe is launching a “Million Genomes initiative’, partly in response to the US’s Precision Medicine Initiative, and partly to combat the fragmentation of research along national lines currently seen in Europe: https://www.genomeweb.com/informatics/million-european-genomes-alliance-proposed-response-obamas-precision-medicine-initiative

Zuckerberg and Chan have committed $3bn to curing all the world’s diseases. As some have pointed out, the sum pales in comparison to what is spent on biomedical research, but the ambition is admirable: http://www.popsci.com/lets-talk-about-how-small-3-billion-is-compared-to-total-scientific-funding

Meanwhile, Microsoft have set their intention to “solve cancer” within the decade, using AI. I’m including this blog post from someone skeptical partly because it has such an on point XKCD comic: http://scienceblogs.com/insolence/2016/09/23/microsoft-vows-to-solve-cancer-in-a-decade-hubris-ensues/

Should babies be sequenced at birth? $25m of new projects announced by the NIH will study the practicalities: https://www.nih.gov/news-events/news-releases/nih-program-explores-use-genomic-sequencing-newborn-healthcare

A “population-based health intervention effort ” in Nevada had thousands of registrants within the first 24 hours of launch, and all registrants will receive free 23andMe reports. The project is a colloboration of Renown Health (an ACO, with rick phenotype data), the Desert Research Initiative (who have environmental data) and 23andMe. https://www.genomeweb.com/molecular-diagnostics/thousands-join-nevada-population-study-get-free-23andme-genetic-tests

Interesting papers

How rare is rare enough to be concerning for a variant? A new paper by the ExAC team suggests some thresholds for the “maximum credible population AF” for different conditions. Spoiler: much less than 5% http://biorxiv.org/content/early/2016/09/02/073114

Using a genomic test to identify which breast cancer patients can skip chemo: http://www.nytimes.com/2016/08/25/science/gene-tests-identify-breast-cancer-patients-who-can-skip-chemotherapy-study-says.html  “The main goal of the study (of 6693 early stage breast cancer patients) was to find out whether women with a high clinical risk but a low genomic risk (23%) could safely forgo chemo… After five years, among those who did not receive chemotherapy, 94.4 percent had no distant spread. Those who received chemo fared slightly better: 95.9 percent had no distant spread.”

The future of baby making became even more exotic with the report of the unnecessary nature of the egg cell (in mice at least): http://www.nature.com/articles/ncomms12676

A good illustration of the importance of gene-environment interactions: children with a particular variant were not more likely to develop asthma than average. But children with the variant who had a viral respiratory infection when an infant are 12 times as likely to develop asthma. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157848

Genomiser, an extension of Exomiser, has been published. It prioritizes non-coding variation in the context of phenotype. http://www.cell.com/ajhg/abstract/S0002-9297(16)30278-6

The Middle East is an interesting population from a genetic point of view because of high levels of consanguinity (100 times higher than the US) and large families. A study looking at 1111 exomes, found e.g. “rare homozygous putative loss-of-function variants in 301 genes, of which a substantial proportion were novel,”: http://www.nature.com/ng/journal/v48/n9/full/ng.3652.html

A delightful paper that dwells on some of the inconsistent uses of language in genomics. e.g. “It is the phenotype or trait that exhibits a given inheritance pattern, not the pathogenic variant. Thus, it is incorrect to say that a variant “is” autosomal recessive (or dominant, etc.) but correct to say it is associated with an autosomal recessive (or dominant) pattern of inheritance.” And calling it Next Generation Sequencing is so yesteryear, now we’re calling it “Massively Parallel Sequencing”. http://www.nature.com/gim/journal/vaop/ncurrent/full/gim2016139a.html

A study of how direct to consumer companies handled data privacy and sharing showed most came up short. The study is also of interest for listing the breadth of concerns that such a company needs to address: https://www.ncbi.nlm.nih.gov/pubmed/27657678

5.6% of people who took a direct to consumer pharmacogenomics test have had prescriptions altered based on the results: http://www.nature.com/gim/journal/vaop/ncurrent/full/gim2016141a.html

You’ve heard of GWAS, you’ve probably heard of PheWAS, but what about EWAS? Epigenome Wide Association Studies are starting to be a thing, such as this one on Schizophrenia, which discovered hundreds of sites differentially methylated in those with the condition, some overlapping with sites previously identified via GWAS: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1041-x

And in another win for omics, a Metabolomic study has shown clear differences in those suffering from Chronic Fatugue Syndrome – their metabolomes resemble those who have infections. The signal is clear enough to suggest a much needed diagnostic method: http://www.pnas.org/content/early/2016/08/24/1607571113.full

The ACMG are planning on updating their list of 56 genes for incidental findings by year end. Subsequent iterations will likely involve pharmacogenomics genes. https://www.genomeweb.com/molecular-diagnostics/acmg-plans-update-secondary-findings-gene-list-year-end-considers-pgx-genes

A new database for DNA modification: http://biorxiv.org/content/early/2016/08/26/071712

Industry News

Health Nucleus, “powered by Human Lengevity Inc” (Craig Venter’s latest project) – an “interactive health platform” completely personalized to you, using your genome. https://www.healthnucleus.com/purpose

Tute Genomics recently launched a campaign via Kickstarter offering DTC genomic services. The FDA swiftly sent them a letter and yesterday the campaign was suspended. The whole exome (~$400) or whole genome (~$1000) service would have not only given customers access to their raw data, but also reports on carrier status, ACMG incidental findings, pharmacogenomics, and “information on well-characterized variant-disease risks for different common or complex diseases”: https://www.genomeweb.com/informatics/tute-genomics-launches-kickstarter-gauge-market-interest-dtc-whole-genome-exome. The note on cancellation: http://www.geneticdirect.com/?p=1749

IDbyDNA, a company that shares a significant overlap of brain power with us at Omicia, has raised a $9m Series A. Their tech enables rapid and exact pathogen detection. https://www.genomeweb.com/business-news/idbydna-raises-9m-series-financing-round

Sophia Genetics and Illumina have started a partnership to address the CLinical Diagnostics European market: https://www.genomeweb.com/informatics/illumina-sophia-genetics-comarket-ngs-solutions-clinical-dx

GenomOncology will work with Genomics England on their cancer samples: https://www.genomeweb.com/cancer/genomics-england-use-genomoncology-data-management-system-100k-genomes-project

Color Genomics, who offer a $250 hereditary cancer test, have raised a $45m Series B. https://www.genomeweb.com/cancer/color-genomics-raises-45m-series-b-financing-offers-patient-families-discounted-testing

A fairly good overview of what Illumina is up to these days, including Helix: https://www.fastcompany.com/3061591/body-os/illumina-owns-the-dna-sequencing-market-now-its-building-an-app-store-too “In the case of Flatley’s own malignant hypothermia, which can result in sudden death while under general anesthesia, a user might query this before deciding on surgery for instance. Or a family might check for an MT-RNR1 m.1555A>G mutation before their child is being treated with gentamicin saving the 1:500 kids with this particular variant from going deaf while in the ICU.”