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.

A 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.

A 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.

A 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.

A 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.

 

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!.

Applications

• 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

• Dan Koboldt has a nice summary of 6 studiesthat pin down genes behind rare disease – an interesting illustration of the diverse set of ways hard-to-solve cases are currently being cracked.
• New genes linked to dilated cardiomyopathy, in a whole exome array based association study of ~3000 cases and ~7000 controls.
• Some variants affecting resistance to anti-depressants.
• Some variants affecting whether your brain will age badlyafter the age of 65
• Another “good news” variant has come to light: a premature stop codon in IL-33 (frequency ~0.65%) has been shown to reduce the risk of asthmain the Icelandic population.
• A study showing that opiate users have excessive histone acetylation, an epigenetic process that regulates gene expression in their brains. The team have already tried a compound designed to limit acetylation in a rat model.

 

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.”

 

Highlights

• 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.