Three topics have dominated genomics happenings. First, polygenic scores: the science continues to mature, there are calls for their rapid clinical integration, there are concerns about their use, and there are commercially available products. Second, how to regulate human germline modification. Third, use of genomics in forensics.

 

Polygenic scores

• The UK Health Secretary has called for prompt rollout of predictive genetic testing across the NHS. Much of his address at the Royal Society was focused on ethics, which he thinks the UK has a proven advantage in. He made his calls under the banner of renewing a “spirit of progress”. Fears that the tech will only be available to white people and of genetic fatalism are also being raised.
• 23andMe launched a diabetes risk feature, based on polygenic risk.
• Genetic Technologies and TGen are partnering to bring polygenic risk tests to the US market
• An interview with Stephen Hsu from Genomic Prediction. They sell polygenic scores for embryos, including Intellectual Disability, where he explicitly mentions using a low score on the Educational Attainment PRS for this purpose. He states that they do not want to be too far ahead of social acceptance for any given screen. He doesn’t think the US is ready to screen for high cognitive ability.
• An estimated ~24% of variance in BMI is due to common genetic variants. A GPS score for obesity, capturing 8.5% of this variance.Those in the top decile weighed an average of 13.3kg more than those in the bottom decile. Those in the top decile had a 43.2% chance of being obese, and those in the bottom decile a 9.5% chance.
• Common genetic variation accounts for ~11% of income, and here’s a pre-print reporting a GPS that captures 2.5% of that variance. The genetic associations were correlated with those for cognitive ability and better mental health. “These results are important for understanding the observed socioeconomic inequalities in Great Britain today.”
• One of the claims of those who tout polygenic scores is that they capture something continuous — not only are more extreme scores predictive of disease, but the scores are also predictive of sub-clinical traits. Evidence for this, in a paper that concludes, based on twin results “The findings suggest that psychiatric disorders are associated with continuously distributed genetic risks throughout the general population.”
• The proportion of the variance of a trait accounted for by genetics is estimated from pedigree (mostly twin) studies, and is called the heritability. Genome Wide Complex Trait Analysis gives an estimate of this variance that is accounted for by common variants. This typically accounts for between a third and a half of the heritability. What about the rest? One possibility is that the pedigree analyses overestimate the heritability. This preprint, from Visscher et al, claims to show that rare variation can cose this heritability gap, using height and BMI as examples. Another preprint gives consistent experimental data in yeast: “Extensive impact of low-frequency variants on the phenotypic landscape at population-scale”.

• A preprint investigating how advantaged and disadvantaged schools treated students differently based on polygenic scores: “Compared to disadvantaged schools, advantaged schools tracked more students with high polygenic scores into advanced math classes at the start of high school, and they buffered students with low polygenic scores from dropping out of math.”

• A preprint giving evidence for its title A Major Role for Common Genetic Variation in Anxiety Disorders (26% for lifetime anxiety disorder)

• Polygenic scores for cognitive traits like IQ and Educational Attainment are confounded by gene-environment effects, especially socioeconomic status. Preprint from Plomin and team. Within family predictions were ~60% lower than between family predictions for these traits, but not for traits like BMI and height. The difference disappeared after accounting for SES, suggesting that SES is part of “passive gene environment correlation” or “genetic nurture”. All genetic influences operate via the environment. Three genotype-environment correlation (rGE) mechanisms:

Passive rGE: “Parents generate family environments consistent with their own genotypes, which in turn facilitate the development of the offspring trait, thus inducing a correlation between offspring genotype and family environment ”  

Active rGE: children select, modify and create experiences

Evocative rGE: children evoke responses in their environment (correlated to their genetic propensities.)

Within family genetic differences can include active and evocative rGE effects, but not passive rGE effects, which are shared within the family.

If aiming just to maximize trait prediction, using between family based scores (i.e. calculated from unrelated individuals) is legitimate. But for causal analysis, including the use of Mendelian Randomization, within family designs are necessary.

• Another pre-print examining the “nature of nurture”, gene-environment correlations in the context of educational attainment which also had access to the polygenic scores for the mothers. They show that both mothers’ and children’s polygenic scores are predictive of parenting style. And also that mothers genetics predicted childhood educational attainment beyond direct transmission, mostly via providing a stimulating cognitive environment.

 

Germline genetic modification: moratorium or no?

• Scientists have called for an international moratorium on on clinical uses of germline editing, which the NIH has backed. First, a fixed term voluntary complete ban, perhaps for 5 years. Then different countries could pursue different paths, but any nation should only consider approving it if a) they notify the international community and engage in consultation about the “wisdom” of the move, 2) have a transparent evaluation procedure for approving applications, 3) have checked that there is “broad societal consensus” on the technology in their country. For (3), they point to the proposal for a Global Genome Editing Observatory. From the article proposing that “This would be an international network of scholars and organizations similar to those established for human rights and climate change. The network would be dedicated to gathering information from dispersed sources, bringing to the fore perspectives that are often overlooked, and promoting exchange across disciplinary and cultural divides.”
• Meanwhile in an interview with The Telegraph, George Church said “I just don’t think that blue eyes and [an extra] 15 IQ points is really a public health threat. I don’t think it’s a threat to our morality.” He compared the discussion post the announcement of Lulu and Nana to the moral panic that preceded IVF. What he does worry about is inequality — which he uses to justify working on making the technology affordable.
• Families with devastating inherited diseases are fed up of the “playing God” argument. 27% fo IVF cycles there are no disease fee embryos.
• The WHO have proposed an international registry for all human genome modification work. This is the first recommendation from a committee tasked with making a “framework for global governance and oversight of human genome editing” They also said that a “vague moratorium” is not the answer.

 

Forensics

• Rwanda is proposing a DNA database of all its citizens for fighting crime purposes. The plan is in its earliest stages, no legislation has yet been passed. In 2015 Kuwait proposed a similar database for fighting terrorism, but it was later struck down by the constitutional court.
• FamilyTreeDNA let the FBU access genetic data without telling its customers, and faced a backlash for it. Now customers can opt out from law enforcement access to their data. But the company doesn’t want its customers to do that, and has launched Ad campaigns on that premise, stating it feels it has a “moral responsibility” to help solve cases.
• Meanwhile, the growth of GEDMatch, the platform that consumers can choose to upload their genetic test results to in full knowledge that law enforcement have access to it, coupled with the ability that up to 4th cousins can be identified from these uploads, is leading to a “National DNA database by default”. So states Natalie Ram in Slate, who calls for ending familial searching, and points to a Bill in Maryland that hopes to do just that.
• An example of DNA being used for more than an ID. In a murder case, police sequenced DNA found on the victim and found that it belonged to a black man, which changed their search strategy. They then asked nearly 400 black men who had been taken into custody in the region for DNA samples, as part of a “Race-biased dragnet”.
• An apartment complex on Long Island is setting up a registry of the DNA of residents’ dogs, and will test dog poop to punish those dog owners that do to clean up after their pets.

 

Science

• Chinese scientists have been added the human gene MCPH1 to monkeys. The gene is a candidate for what makes us distinctly human, and the monkeys did better on a short term memory test. The authors were not able to find a Western journal to publish in.
• A preprint from the Church lab on making thousands of edits at once
• MC4R is involved in appetite. Those with loss of function mutations have a higher likelihood of being obese. New data show that those with gain of function mutations weigh less than average. A person 1.7m tall who had one gain of function allele in the gene MC4R (6.1% individuals) weighs an average of 1.1kg less than someone with no such mutation. For those with two such mutations (0.1% individuals), it is 2.5kg less. A write-up by the NYT, summarized thus: “Together, the studies [this and the polygenic score mentioned above] confirm a truth that researchers wish more people understood. There are biological reasons that some struggle mightily with their weight and others do not, and the biological impacts often are seen on appetite, not metabolism. People who gain too much weight or fight to stay thin feel hungrier than naturally thin people.”
• Some features of brain “life” were restored in pigs four hours after death. This included circulation and some cellular functions. The researchers developed “a surgical procedure, perfusate, and custom pulsatile-perfusion device”.
• In a proof of concept study, 5% of mice survived a CRISPR cure for a lung disease administered in utero. The CRISPR components were injected into the amniotic fluid, which gets inhaled by the lungs. The edit, a  gene knockout, were restricted to the lungs.
• Genetic analysis of a woman who feels almost no pain has revealed that her body does not break down anandamide, a substance that acts like cannabis in the body. The gene involved is FAAH. Her combo of two mutations also makes her happier, more forgetful, and not susceptible to stress.

 

Applications

• In Louisville, Kentucky, an unmarked van has been going round and giving homeless people $20 in exchange for a DNA sample via check swab. In at least some cases they said it was for a cancer test. They claimed they were operating with Passport Health (which manages Kentucky’s Medicaid program) and took insurance information. Passport deny any involvement. Now the Kentucky Attorney General has asked for people who gave samples to call a fraud hotline. It seems that no laws were broken, and it is suspected that insurance fraud may be attempted.
• First three-person baby born. A team at in Greece used maternal spindle transfer for the first time clinically.
• First US CRISPR trial for cancer are underway.
• 8 infants with SCID (bubble boy disease) were treated with a gene therapy and appear cured
• The International Society of Psychiatric Genetics released updated guidelines for the use of genetic testing in clinical care. It failed to reach consensus on a couple of issues, including whether to offer adults CNV testing given that this doesn’t change management, and whether to offer pharmacogenomic testing.
• A child’s “right to an open future” is used to argue against predictive testing for children. A group from the Clinical Sequencing Exploratory Research (CSER) Consortium Pediatrics Working Group argues that there is no such right — instead, predictive testing of children would be ethically permissible if benefits outweighed risks.

 

Regulation

• The Genetic Information Nondiscrimination Act (GINA) outlawed genetic discrimination in health and employment, but not in life and disability insurance. A Bill is going through Florida to outlaw genetic discrimination in life insurance.
• Oregon is considering a Bill to make it much easier for those convicted to access DNA testing
• Australia is charting a middle of the road regulatory approach for genetic editing of plants, animals, and human cell lines. If no new genetic material is incorporated, it will not regulate. Contrast Europe, where genetic editing was judged to fall under (regulated) genetic engineering standards, and the US, where the USDA will not regulate gene editing plants at all.
• The FDA have asked Inova, a Health Care System, to stop marketing its pharmacogneomics test without its approval, on the basis that it covered more than the pharmacogenomics indications present on FDA drug labels. Their test also covered genetic-drug interactions as classified by industry guidelines, and they had developed it on the understanding that the FDA would not regulate under these circumstances. Inova’s response was to say that they will cease offering their test rather than seek approval. The FDA has been making moves to regulate laboratory developed tests (LDTs) for a while. This debate is about to reheat.
• After 25 years of legal hurdles, AquaAdvantage, salmon genetically modified to achieve full size in 16-18 months compared to the normal 30 months now have the green light to be farmed in Canada. And the FDA have said they can sell them in the US, though there is a pending lawsuit.