A vast amount of research has started to understand how human genetics interacts with the new coronavirus. 

The below is written with what is an ever growing interest for me in my work in bioethics: the significance of individual biological difference, and how we let this influence our lives; and the difficulties that stem from the use of the population concept. I have drawn attention below to the all-too-easy-to-make differences between populations that are appearing in the literature.

Humans react very differently to infection with SARS-CoV-2. Some of this is because of genetic differences. Understanding these differences could help our understanding of disease processes — severity, outcomes, how the immune system interacts with the virus. This could lead to better disease management, possibly by suggesting therapeutic approaches. It could also help us understand patterns of infection, possibly informative for vaccine development. These use cases are the biggest motivation. They don’t rely on any of us learning our own relevant genetic information.

Understanding what makes some people more and less susceptible to severe disease could also be used directly. Genetic information is often used in the prescription of pegylated interferon α and ribavirin for chronic Hep C infection. Finding who is least susceptible could be useful for clinical trial design, particularly if we opt to purposefully infect research subjects in a challenge trial design. Finding who is most susceptible could help identify who has to take extra precautions. Recognizing that a diverse array of genotypes can have large impacts could ensure that individuals with all those genotypes are represented in therapy trials and vaccine trials, so we know that results generalize.

Before we turn to human genomics, what do we know about the virus’s genome?

Before SARS-CoV-2, 6 human coronaviruses were known: SARS, which killed 774 of 8096 infected in 2002-3; MERS, which killed ~600 of ~2000 infected starting in 2012; and four others that cause milder symptoms, which collectively account for a third of all colds. There are also hundreds of coronaviruses that infect other animals, notably bats. In 2013, a bat virus very close to SARS was identified, suggesting direct transmission from bats.

The first genome of the new coronavirus was published on January 10: ~30,000 bases, 14 ORFs encoding 27 proteins. The NYT produced a beautiful tour of the viral genome.

On 21 January, a group posted to the bioarxiv a theory that the virus may have been engineered in a lab. Others pointed out mistakes in the analysis, and it was quickly retracted.

The first report of viral sequences from nine Wuhan patients showed 99.8% sequence identity to each other, and hence a recent common origin. It also showed sufficient divergence from SARS-CoV to be classified as a different virus. 

Based on homology to SARS-CoV, SARS-CoV-2 was predicted to also use the human protein ACE2 to enter cells. The receptor binding domain on the spike protein has a strong effect on infectivity. (It is known which mutations might lead to greater infectivity; it is hoped these will not be selected for.)

Multiple sequence alignment has been used to trace how the virus is spreading. This is a key technique in “precision public health” which relies on using slight changes between pathogen genomes to trace how the infection spreads through populations. See a global effort called NextStrain— with lots of beautiful graphics. A recent (but non-covid) review of pathogen genomics. The CDC has been a late adopter compared to e.g. the UK, but there are several very large scale efforts using next generation sequencing for pathogen tracking in the US. The UK announced a £20m effort to track the pathogen using viral genomics. Another great graphical piece from the NYT showing how the virus has gained mutations, and how this can let us track the virus.

An April 29 preprint showed two clades, six subclades, and some evidence of convergent evolution to affect how strongly the spike protein binds to ACE2. Mutations in some subclades could evade some current tests.

(Of interest: As reported by MIT Technology Review, 20 years ago it was demonstrated that, starting with viral DNA, a virus would “reboot” in a cell. That meant that as soon as the viral genome was published, any lab with access to something that could “print” DNA, and that had the know how to go from there, could make the virus (and any variant thereof). Only a few places can print DNA. They can choose whether to fulfill an order. Part of the process is that they compare incoming orders with a database of known pathogens (e.g. polio), to give one layer of control.)  

Host genomics

COVID-19, the disease that can result from infection with SARS-CoV-2, is a product of the virus, the host, and the environment. The genome of the host can affect the impact of a pathogen, with both rare and common human variation known to play a role. The most famous example is the allele for sickle cell anemia: heterozygotes are protected from malaria. Another famous example is CCR5‐Δ32 which confers resistance to some HIV strains (this was the edit made to the first genetically engineered humans, born in 2018). 

A 2017 review stated “Despite their limited application in the field, GWASs [genome wide association studies] have provided valuable insights by pinpointing associations to both innate and adaptive immune response loci, as well as novel unexpected risk factors for infection susceptibility.” It also stresses that heterogeneity across populations is particularly important in the setting of host response to infectious disease. Things also get complicated by the presence of viral strain – host genotype interactions. We have evidence from this in HepC.

A 2016 study titled “Genetic Ancestry and Natural Selection Drive Population Differences in Immune Responses to Pathogens” showed that, when exposed to listeria and salmonella, many genes showed differential expression in white blood cells between individuals of European ancestry and individuals of African ancestry. They traced these differences to genetic variants, and further argue that the differences between populations are due to recent natural selection.

How important are genetic differences in understanding the differences in how SARS-CoV-2 affects individuals? An early estimate of the heritability of susceptibility to SARS-CoV-2 infection puts it at about 50%. This is hard to estimate as there are so many confounders, for example poverty.

The standard tools for identifying which genetic variation makes a difference are genome wide association studies. A preprint shows that early variants that show up as genome wide significant in the UK are associated with higher educational attainment and better health, and hence probably capture who was traveling, rather than anything about disease biology.

Which genes are known to be involved in how SARS-CoV-2 affects the body? 

• Angiotensin-converting enzyme 2 (ACE2), which normally helps regulate blood pressure and protects the lungs from injury (which makes it a bad drug target!), acts as the receptor for the spike protein. It is expressed in the lungs, heart, kidneys, blood vessels, and intestines. ACE2 expression is positively correlated with infection and increased in older patients, in males, in smokers, and in the cell types known to be affected by the virus. Increased expression may also be linked to T2D and some other traits. It is on the X-chromosome. For most X-chromosome genes, the second copy in females is inactivated. But some genes escape this, and ACE2 is one of them. But, complicating the story, expression levels tend to be higher in males.
• At least two other proteins that also help with virus entry into the cell: transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL). 
• BSG (CD147) is a receptor involved in binding SARS-CoV protein binding
• FURIN encodes a protease which can cleave the spike protein of SARS-CoV-2 (but not SARS-CoV)
• It is not clear what is driving morbidity and mortality, but a contender is an over-reactive immune response. Some proteins involved in immune response, including Interleukin 6 (IL6, a pro-inflammatory cytokine), its receptor and co-receptor (IL1R), and the cytokine TNF’s response pathways, are also thought to be relevant.

What human variation has already been identified that makes a difference for COVID-19?

• ACE2
  • A first look at ACE2 variability concluded that “the differences in AFs [allele frequencies] of ACE2 coding variants among different populations suggested that the diverse genetic basis might affect ACE2 functions among populations.”
  • Structural modeling revealed a couple of ACE2 rare variants that affect the structure sufficiently to affect virus binding, and hence possibly confer resistance (rs73635825 (S19P) and rs143936283 (E329G)) 
  • Previously, variation in ACE2 has been linked to hypertension and retinopathy in type 2 diabetes. Because of this prior attention, it is known that a SNP effects expression levels
  • A preprint from a UBC group looks at variants predicted to effect binding of ACE2 to the spike protein, finding that small numbers of people will have rare variants, with percentages depending on ancestry, and (because females are mosaic) sex “genotyping of this class of alleles is justified in cases of atypical SARS-CoV-2 diseases”
• The Interferon Lambda Region has a role in controlling the expression of ACE2. Polymorphisms in the region have been linked to ACE2 expression levels in diseased tissues (preprint from an Oxford group). Variation in this region has previously been associated with Hep C infection outcomes (but with effect varying by virus genotype). The protective allele is found more frequently in East Asians and its absence in those of African ancestry. They conclude “the overall impact of this polymorphism on the clinical course should be assessed, especially given the very variable distribution of IFNL4 alleles in different ethnic groups”
• TMPRSS2
  • A preprint from Italy found different haplotypes between East Asians and Italians, with two rare alleles of interest predicted to induce higher levels of TMPRSS2 in Italians. One suggesting possible regulation through androgens (and hence possibly linked to sex differences), and the other already linked to increased susceptibility to flu.
  • A preprint from the LungMap consortium found evidence of increased expression of TMPRSS2 with aging, and identified a regulatory SNP that contributes to expression levels.
• Interferon-induced transmembrane protein 3 (IFITM3) – a variant linked to more severe disease. The study from China compared mild to severe cases and found the homozygous variant rs12252 was much more common in the severe cases (p = 0.00093; OR = 6.37). The variant was previously associated with flu severity, and is found at much higher rates in those of East Asian ancestry (e.g. carried by ~26% of the Beijing population). 
• HLA proteins. A class of human leukocyte antigen (HLA) proteins sit at the cell surface, presenting short sections of protein (peptides) for recognition by T-cells. If the T-cells recognize non-self, they react appropriately. Which peptides are shown? That depends on what’s in the cell — if a virus is present, it can include sections of virus proteins. And it depends on the precise structure of the protein’s binding grove, which is hyper-variable between humans. The extent to which an individual’s HLA cells have binding groves that bind bits of the viral proteins could therefore affect the body’s immune response is. 
• Blood groups (A more susceptible, O less so)
• Meanwhile, polygenic scores for disease severity have already been prouced

Several large scale studies are starting

• 23andMe asked its customers to opt in to a study of the genetics underpinning disease severity. Ancestry have done likewise.
• The UK Biobank, which hundreds of researchers have access to, is adding the results of covid testing to the already very rich genetic and medical information.
• Decode genetics, which sequenced the genomes of half the population of Iceland, is testing much of the population for COVID. They’re now sitting on a lot of relevant data.
• A group led by Andrea Ganna in Finland, pulling together studies from around the world
• A study based out of Rockefeller University to look at inborn errors in immunity, focused on the young individuals who became seriously sick. The lead researcher, Jean-Laurent Casanova, has been conducting similar studies for decades.

There have also been some commitments to the ideal of data sharing

• The Wellcome Trust called on institutions to commit to data sharing, modeled on the 2016 Statement on data sharing in public health emergencies 
• Covid-19 data sharing portal, an EMBL project
• The COVID-19 Host Genomics Initiative is acting as a coordination point for studies. Results of meta-analyses are expected in May.

Notes

• Some of these references are to preprints, which are not peer reviewed. Others have been rushed through printing. I am pretty confident that not all of this will stand the test of time.
• So much is standardized in the genomics workflows, and so much of the data is publicly available, that it is very easy to put out papers that look vaguely sensible. Here is a preprint looking at ancestry differences, which I remain very unconvinced by

I will cover coronavirus separately. In the meantime, a lot has been happening in genomics more broadly. I’ll draw your attention to:

1. Ongoing controversy about Precision Medicine. Two pieces question the prominence it receives Precision medicine: course correction urgently needed and Promises and perils of using genetic tests to predict risk of disease. Meanwhile The Personalized Medicine Coalition has helped put together a new bipartisan caucus to advance support for personalized medicine in Washington.
2. A host of new common disease/complex trait work (separated into its own section below), including GWAS for self-reported childhood maltreatment, income, alcohol intake, lifespan. A few papers that have looked at including polygenic scores in clinical models, with mixed results.
3. A remarkable amount of legislative efforts, including a Bill on the Governor of Florida’s desk that would close some GINA loopholes, and efforts in Utah, New Jersey, and California
4. DNA from detained immigrants is being added to the federal national DNA database, CODIS, which was originally established to track violent federal offenders

 

Science

• From October, prime-editing, akin to “search and replace” rather than “cut and paste”, which doesn’t require a double strand break “Prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases.” In the first few weeks post the publication of this article the researchers were inundated with requests for constructs.
• Some updates from All Of Us: 339,000 consented participants, 265,000 completed the full protocol, 50% from racial and ethnic minorities, 80% from populations underserved in biomedical research. “This is more than just a data resource. It’s an ecosystem” that includes data analysis tools and participant outreach.
• Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, reporting on the matched tumor-normal sequencing of 2,658 individuals. Key findings included: average of 4-5 driver mutations per cancer; only 5% tumors lacked any identified driver mutation; large rates of  chromoplexy (17.8% of tumours) and chromothripsis (22.3%); change of mutational signature over time in 40% of tumors; driver mutations can occur years before cancer diagnosis. 
• The NHGRI have published their draft Genomics 2020 strategic plan. They invite comments.
• Anti-CRISPRs exist in the wild, as part of the viral counter-attack to the bacterial counter-attack that is the main function of CRISPR systems in bacteria. There are also several other attempts to produce a “stop button” for gene editing, which should have as a by-product editing which can be better targeted to particular cell types and to reduce off-(sequence)-target effects. (Link to an easy to read nature news feature summary).

 

Polygenics: Common diseases/complex traits

• Two studies in JAMA showing no and limited improvement in a clinical risk score when including polygenic scores for cardiac disease
• A study in the Finnish Biobank of polygenic scores shows increased predictive power over clinical models for T2D, Breast cancer and prostate cancer, and improved reclassification over clinical thresholds for all diseases tested (those plus coronary heart disease and.atrial fibrillation)
• A meta-analysis of 42,000 individuals found “significant associations between childhood psychopathology and adult polygenic scores of major depression, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index but not bipolar disorder.”
• Lifespan heritability is estimated to be 23-33%. Some of this comes from the effects of rare protein truncating variants.
• Looking across the UK, Japan, and Finland biobanks, researchers looked at how polygenic scores affected lifespan, claiming that this shows “new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.”
• GWAS of alcohol intake.
• GWAS for income, estimating 7.4% heritability, and constructing a polygenic score capturing 1.2-2.0% of the variance in household income. The conclusion, “These results indicate that, in modern era Great Britain, genetic effects contribute towards some of the observed socioeconomic inequalities.” stresses that these numbers are non-zero, rather than that they are very small (which it equally could have done).
• A GWAS for self-reported childhood maltreatment. Why, you might ask? “A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.” They speculate about a possible role for FOXP variants they identified in “externalizing traits”, which include overactivity, poor impulse control, noncompliance, and aggression.  
• A polygenic based score for stroke identified 0.25% of the population at threefold increased risk. This is much less discriminatory than , for example, coronary artery disease. 
• A computational method to improve polygenic score accuracy in admixed individuals, which basically a) breaks an individual’s genome into ancestry derived blocks, b) applies the ancestry relevant effect sizes to that block. This should lead to less biased estimates even if good GWAS data is only available for one of the ancestries (European).
• A preprint focused on making polygenic scores more interpretable, through identifying genetic drivers of risk: “For example, we find that BMI polygenic risk factorizes into distinct components relating to fat-free mass, fat mass, and overall health indicators like sleep duration and alcohol and water intake. Most individuals with high dPRS for BMI have strong contributions from both a fat mass component and a fat-free mass component, whereas a few ‘outlier’ individuals have strong contributions from only one of the two components.” 
• Genomic Prediction, the company that will screen embryos for polygenic scores, published a piece reporting that for Type 1 Diabetes, a 45-72% reduced risk using a polygenic score when choosing between an affected/unaffected sibling pair compared to random. Contrast this study with the article Screening human embryos for polygenic traits has limited utility which focused on expected gain, i.e. enhancement, rather than screening out high genetic risk for a disease. 
• Intuitively, if you have less accurate phenotyping, you’re less able to identify genetic effects. Proof of that for depression, where use of “minimal phenotyping” led to identifying different genetic architecture than full on medical diagnoses.
• A review about unpicking the causal effects of genetics in genotype-phenotype correlations. Population stratification, assortative mating, and dynastic effects are all captured in these correlations.
• The authors of the GWAS of same-sex behavior defend their research, arguing first that their phenotype is health related, and second that “We believe that when broad biobank consent is used, institutional bodies (such as the UK Biobank’s Board and its Access Sub-Committee) must take responsibility for approving specific research requests rather than expecting participants to understand all such details for possible research projects.” 

 

Applications

• Ancestry has laid off 100 people, 6% of its workforce. 23andMe also laid off 100 people, 14% of their workforce. Both cite declining consumer demand. Veritas halted its US operations due to financing issues.
• The Pentagon warned military personnel not to take DTC genetic tests: GINA’s protections do not extend to military personnel: “The unintentional discovery of markers that may affect readiness could affect a service member’s career.” Separately, the data’s existence could “potentially create unintended security consequences”.
• The first use of CRISPR inside the body, for a blind patient as part of a trial of an approach by company Editas. Results will take months. 
• Apple is offering free genetic testing to all its SIlicon Valley based employees.
• A public opinion survey asked about financial expectations for contributing data to genomic databanks, 11.7% no payment, 50.6% with payment, and 37.8% never. Those who wouldn’t expect payment would pay $75 for results, those who expected payment expected $95 on top of a report. 
• The American Society for Human Genetics commissioned a public survey. I thought this was the most interesting finding: “Thirteen percent report having taken a direct-to-consumer genetic test; 8 percent had a genetic test through a hospital or research center; 5 percent had received genetic counseling; and 5 percent had participated in research requiring a blood or saliva sample.”

 

Regulation etc

• He Jiankui, of Lulu and Nana fame, and two colleagues, were sentenced to jail sentences in China for “illegal medical practice”
• A call for “An international code of conduct for genomic data.” To cover: identifiability; broad consent; return of individual findings, portability and access; withdrawal; and compelled disclosure. “A first step would be to convene a meeting to determine the topics the code would touch on, the best way to consult research participants about their needs and a decision-making process that will allow the text to be finalized in a timely way.” “further regulatory uncertainty risks stalling new genomic analyses and undermining people’s faith in scientific collaboration for the public good.”
• US federal and foundation funding has been far higher for cystic fibrosis than for sickle cell anemia. The former mostly affects European ancestry individuals, the latter African ancestry individuals.
• Bioethicists suggest a duty to reinterpret genetic data
• Establishing the International Genetic Discrimination Observatory, “a unique network of researchers and other stakeholders dedicated to researching and preventing genetic discrimination worldwide. It is forward looking, with a broad purview that includes discrimination based not only on genetic information but also on other emerging forms of predictive health data. Its broad approach to genetic discrimination is framed by recognized human-rights principles including respect for autonomy, dignity, privacy, the right to science, and the right to know or not know about genetic results.” In lieu of regulation, they mention “moratoria, administrative policies, governmental decrees, mandatory ethics regulations, and agreements between organizations and patient groups”.
• Legislative efforts
  • A Florida Bill banning genetic discrimination in life insurance, lon-term care insurance, and disability insurance, passed both houses (with very few dissenting voices) and is awaiting governor signature. Insurers can only use genetic testing results if they’re part of a medical diagnosis. It will be the first state to prohibit such use.
  • Proposed California legislation to restrict genetics DTC companies use of data
  • New Jersey has proposed legislation aimed to secure greater genetic privacy, it would make DNA information the property of the person analyzed. “With this legislation, New Jersey would join 24 other states that require informed consent to disclose genetic information. The state also would become sixth after Alaska, Colorado, Florida, Georgia, and Louisiana in explicitly defining genetic information as personal property, and second only to Alaska in extending personal property rights to DNA samples.”
  • Efforts in Utah to prevent law enforcement access to consumer DNA databases.
• We each leave a metabolite trail, not protected by GINA.
• A nice summary of GINA and employment. There hasn’t been a single successful lawsuit alleging genetic discrimination by an employer, something that the Federal law GINA protects. There have been plenty of charges files with the Equal Employment Opportunity Commission, who have filed 12 cases as a result. Most of these are not due to employers getting genetic data, but family medical history data. But GINA has worked as a privacy statute. GINA covers unmanifested conditions, and the ADA covers manifested conditions that cause disability, leaving something like prediabetes in limbo. 
• DNA and law enforcement
  • DNA from detained immigrants will be entered into the FBI’s CODIS database. This database was originally designed just for violent federal offenders but has been repeatedly expanded, including to arrestees never charged. It currently contains 20 million individuals, of which 5 million are arrestees, and 40% are black. Collecting detained immigrant’s DNA will further skew the proportion of minorities represented. 
  • Local law enforcement agencies have laxer standards about whose DNA they keep. The NYPD is going to delete samples that never led to a conviction that are at least two years old.
  • Epigenetic clock tests, which can predict an individual’s age within a few months, are drawing ethical concern around their potential use on migrant minors.

I started a fellowship at Harvard this fall, and it’s taken me a while to find the time to sit down to do a round-up. There’s been a torrent of news, covering DTC player expansions, major new initiatives, and law enforcement’s use of DNA technology – as well as a host of other topics. We’re a year out from the birth of the first genetically modified babies, and full swing into the polygenic turn. Diversity remains a governing watchword.

 

Controversy

• Following on from the genetics of non-heterosexuality paper, GenePlaza added an App based on the genetics of non-heterosexuality paper published earlier this year. Ben Neale, lead author of the paper, wrote to GenePlaza urging them to take it down, saying that the paper explicitly stated that individual level prediction was impossible.The App is no longer available. A whole set of other Apps based on polygenic scores continue to be available. Scientists who claim that individual usage in this context is outright wrong are involved in individual usage in clinical applications. This is an ethical line, not a scientific one.
• Researchers who helped gather African genotype data in collaboration with the Sanger have demanded the samples back. They heard that there was a commercial tool planned, and say that this wasn’t within scope of the data sharing.
• One year on from the CRISPR babies
  • He Jiankui’s paper about Lulu and Nana was turned down from two journals and from BioArxiv for ethical reasons. Now MIT Tech Review has published excerpts, alongside commentary.
  • An ethicist makes the case for germline modification, on utilitarian grounds.
  • Russian authorities have called gene edited babies premature, a long awaited announcement from a country with no laws banning the procedure, and with a scientist who has indicated he would go ahead with a green light.

 

Science

• New initiatives
  • The 500,000 genomes of UK BioBank participants will be sequenced, at a cost of £200m, £100m of which will come from pharma companies. Target completion date is Summer 2021.
  • The UK is working on sequencing 5 million genomes. And Matt Hancock, the Health Secretary, wants to do newborn sequencing ASAP, “Predictive, preventative, personalised healthcare – that is the future of the NHS – and whole genome sequencing and genomics is going to play a huge part in that.”
  • The International Common DIsease Alliance launched, aiming to tackle “maps to mechanisms to medicines”. Eric Lander describes this as the next major push of the genomics community.
  • The NIH is funding, to a tune of about $30m, the construction of a new “pangenome” reference genome, to be based on 350 individuals of diverse ancestries.
  • The NIH is planning a Polygenic Risk Score Consortium, with $34m available (here and here). 
• A study of 426 people from 13 African countries shows just how diverse genetic ancestry is in Africa, and hence how inadequate just incorporating one ethnic group from Africa is in studies.
• Lupus disproportionately impacts black women. Epigenetic differences have now been tied to this difference, “highlighting the lack of information scientists have regarding racial differences on the genetic level”. The familiar refrain about more diversity in samples follows.
• Genetic variation that leads to less need for sleep. Two members of a family with this variant need much less sleep – 5.5 and 4.3 hours – than average. This reminds me of the plot of Nancy Kress’s Beggars from Spain, which imagines children genetically engineered to need no sleep. 
• Results of levels of trust in data sharing amongst the public are out from the Your DNA Your Say project (N ~9000, across USA, UK, Canada, Australia). 19% would trust the government of their country.
• A write-up of a study that purports to use AI to find three gene and environmental networks that shape personality.
• An antisense oligonucleotide therapy developed for one girl seems to have helped her. This is true personalized medicine. In an editorial, FDA members, ask “In these “N-of-one” situations, what type of evidence is needed before exposing a human to a new drug? Even in rapidly progressing, fatal illnesses, precipitating severe complications or death is not acceptable, so what is the minimum assurance of safety that is needed? How persuasive should the mechanistic or functional data be? How should the dose and regimen be selected? How much characterization of the product should be undertaken? How should the urgency of the patient’s situation or the number of people who could ultimately be treated affect the decision-making process? In addition, how will efficacy be evaluated?” They hint at something that I think has to be the way forward: “Approvals as variations on a well-characterized archetypal product might be feasible if the interventions are closely related.” 
• A preprint pointing to the genetic correlates of general intelligence, g. Various different cognitive measures are correlated; so is the underlying genetics.
• A large scale study looking at the genetics of schizophrenia in European and East Asian populations. To quote their major conclusions:
  • “When a single population is used to identify the disease-associated loci, the discovery is skewed towards disease-associated variants that have greater allele frequency in that population. When multiple populations are used, disease-associated variants are equally represented across the allele frequency spectrum in these populations. This shows that including global samples improves the power to find disease associations for which the power varies across populations.”
  • “For traits such as body mass index and autoimmune diseases, we observed heterogeneity across populations in genetic effects, which may point to interactions between genetic associations and environmental factors and/or other genetic loci. In contrast, for schizophrenia, we did not find significant heterogeneity across EAS and EUR ancestries.”
  • “Despite a cross-population common variant genetic correlation being highly consistent, we found that polygenic risk models trained in one population have reduced performance in the other population due to different allele frequency distributions and LD structures. This highlights the importance of including all major ancestral groups in genomic studies, both as a strategy to improve the power to find disease associations, and to ensure that the findings have maximum relevance for all populations.”
• In a perspective piece, Reading tea leaves? Polygenic scores and differences in traits among groups, Graham Coop explains “the ways in which issues of causality, stratification, gene-by-environment interactions, and divergence among groups all complicate the interpretation of among-population polygenic score differences”
• The BabySeq project returns adult onset information to families of newborns. But ethicists continue to argue that this risks a child’s right to an open future.
• CRISPR could be a major weapon in the antibiotic arsenal.
• Can Biology Class Reduce Racism? A class designed to communicate the complications of genetic science to high school students shows promise.

 

Applications

• Ancestry is going to offer health information to its customers. The tests will be ordered through a physician (who will not interact with the patient), and will include genetic counseling. The focus will be on 17 genes. Customers will be able to a SNP Chip based add on to their ancestry results for about $49, or opt in to NGS exome testing, which has an initial $199 price tag and a $49 per six months for them to reinterpret data. The initial focus of this will be on the same 17 genes. The subscription model is a bold attempt to address the issue that the underlying evidence base is changing. No doubt they’ll also be excited that the once every six months will increase customer engagement too.
• 23andMe has partnered with TrialSpark for recruitment to clinical trials. Potential research participants would be identified based on their phenotype and/or genotypic information. 23andMe can capitalize on its very engaged user base: “The company estimated that currently, more than 80 percent of its customers have opted to participate in research and over 60 percent have logged in to their account in the last 90 days.”
• Anna Wojcicki, founder and CEO of 23andMe, thinks that we just need time for people to get used to the idea of sharing genetic information, just like we needed time to get used to putting our credit card information online. “The reality is with a new technology, it just takes time for people to be comfortable with it.”
• SNPedia and Promethease have been bought by Israeli based myHeritage
• Nebula Genomics is offering anonymized sequencing. Enabled by blockchain.
• Illumina and the Broad are collaborating on a GATK based variant calling platform. The results will be open source, but Illumina will also develop a proprietary version that will run on its hardware Dragen (formerly of Edico).
• Wired reports on the progress made by 54gene. Operating in Nigeria, the VC backed company is getting access to samples and medical records through additional consent given by participants of other clinical trials. They’re on track for 200,000 samples by the end of 2020.
• I’ve written about Genomic Prediction, the company that will test embryos for a range of polygenic scores. They report their first pregnancy post embryo polygenic profiling. This is a long time after their test has been on the market.
• Genomics Medicine Ireland  is under increasing scrutiny – it aims to sequence 10% of the country’s population, and unlike other major national initiatives, it is a private enterprise.
• China is using tech for predicting faces from DNA on the Uighur population.
• Performance enhancing probiotics tailored to an athlete’s microbiome? There’s a startup out of Harvard working on it. 

 

Regulation etc

• DNA and law enforcement
  • The LA times reports on a backlash against the use of rapid DNA analyzers as part of booking, mostly because of a rushed roll out, rather than in principal concerns. “Roughly 30 states allow immediate DNA testing of crime suspects — including California, which permits it for all felony arrestees. Several states have no such laws, or limit such testing to only the most serious felony cases.” 
  • Department of Justice proposals to collect DNA from everyone who crosses the border illegally. 
  • An interim Department of Justice policy restricts the use of genetic genealogy to a) cases where there has not been a match in CODIS, and b) violent crimes or unidentified remains.
  • GEDMatch, the database that individuals can upload their own data to, gave its users the choice whether to let their data be accessible to law enforcement. Only 185,000 of over 1 million did so. Now, a Florida detective was able to secure a warrant to search the whole database. The concern is that this will set a dangerous precedent, giving law enforcement confidence to go after 23andMe and Ancestry.com.
• Someone serving a sentence for murder is being allowed to appeal on the basis of carrying the allele of MAOA associated wuth heightened aggression.
• A right to know? Or not? In the UK, a woman is suing because she was not told that her father had tested positive for Huntingtons, based on his wishes. In Germany, a woman is suing because she was told that her ex-husband tested positive.
• New regulations will make it easier for Apps to get your health data. But once they have it, it will not be subject to much by way of privacy protection, as the Apps will not be covered entities under HIPAA.
• The Regulatory and Ethics Work Stream (REWS) of the Global Alliance for Genomics and Health (GA4GH) has updated its policies, which touch on all aspects of data sharing. The aim, as explained by group chair Prof. Bartha Knoppers, is to “provide guidance that will support the human right to benefit from this work”
• GDPR requires “adequacy” determinations with other countries before data can flow freely. The first such one has been granted, to Japan. The decision reflected a willingness on the part of the EU to be flexible, in instituting supplemental rules.
• In France, all DTC genetic tests are banned, with criminal penalties. This includes genealogical tests. Some want to keep it that way for now, because if the ban is lifted, foreign companies will rush in.

The polygenics of sexuality (see below) has been in the limelight. I appreciated that the dialogue around this study got into some of the “so what” of this type of work. In a post on Medium I reflect on the fact that we seem to be a bit picky and choosy about which traits we are willing to embrace as having a genetic etiology. A recently published study reveals some other biases: Antisocial behavior is judged as less genetically influenced than prosocial behavior. Probably because people wanted to hold others to be blameworthy for their actions.

I continue to think that we’re racing into a future where we have some handle on biological differences between individuals (via probabilistically predictive scores of various types, genetic and otherwise), and that we lack the necessary frameworks for knowing what to do with this information. Putting my time where my worries are, starting today I’m officially employed to think about exactly these questions. 

 

Science

• The “no single gay gene” study in Science, covered by numerous news outliets, found that the trait ever versus never had same sex sex is ~32% (95% confidence interval 11-54%) heritable, and is polygenic. From a scientific point of view, that result is completely unsurprising, just shoeing that this trait is like all others studied. One thing that was different about this trait: male-female genetic correlations were considerably less than the usual one. Secondary results from the study included that personality traits, mental health disorders, and risky behaviors were genetically correlated with the trait, but not physical traits. They also looked at the proportion of same-sex to total partners, and found that this trait was not that highly correlated with the ever/never had same sex sex (0.73 for men, 0.52 for women). Their conclusion? Sexuality is complex, and can’t be captured by a single dimension, as scales like Kinsey’s try and do. The study is an interesting case example of how ethics was engaged with. 
• Polygenic scores cannot be interpreted as a “genetic endowment” because the predictive power can come from a number of other sources: population stratification, assortative mating, and genotype-environment correlation (rGE). They found that the predictive power of polygenic scores for cognitive traits was higher (by 60%) between families than when looking at non-identical twins. But if socioeconomic status was controlled for, much of the difference disappeared. They conclude that socioeconomic status contributes to the between family predictive power of cognitive polygenic scores, acting as an “environmentally mediated parental genetic effect”, a type of genotype-environment correlation. 
• A preprint that covers the potential effects of selecting embryos on the basis of polygenic scores. When selecting between ten embryos, with 20% of the variance captured by the polygenic score, the gain (selecting for highest score embryo versus average embryo) would be ~0.5 of a standard deviation, with a 95% confidence interval of -1.2 to 2.3. Compare to the standard deviation of 6cm for height and 15 IQ points. 
• A preprint of a large (135,000) Finnish study on polygenic scores for a few major diseases. Comparing the top 2.5% to the middle 20-80%, hazard ratios of 2.0-4.3 (depending on disease). They conclude that the performance of the polygenic scores was similar to established clinical risk scores.
• An example of sociogenomic research: finding that some polygenic scores are associated with exposure to bullying.
• A preprint that points to a way polygenic scores could be made clinically relevant: by focusing on the variants that contribute to polygenic scores that also fall within gene sets tied to particular drugs. 
• Polygenic score for Alcohol abuse, 
• More evidence for the common genetic underpinnings of various psychiatric disorders.
• Some genes in humans are up-regulated after death

 

Applications

• Erik Parens and Paul Appelbaum consider the evidence for the widely predicted negative psychosocial impacts of genetic testing. Years of study have shown that individuals do not end up more depressed or anxious or stressed (though there may be transitory effects. Note the recent Hastings Center Special Report containing many papers on this topic). They see a path forward “Using more subtle measures than merely asking people if they feel depressed or anxious” to show that “genetic results can affect people in real ways.” Here are the examples of this newer generation of work that they point to:
  • A study that shows those were APOE e4+ and knew rated their memory worse and performed worse on a memory test than those who were positive and didn’t know. 
  • A study where individuals were told whether they had a genetic variant associated with decreased exercise capacity independently of their genetic results found that those told they had the variant performed worse.
  • A study that shows the impact of perceived genetic cause of obesity, with subjects more likely to eat more if they thought it was genetic.

• The WSJ points out that patients may not realize that those who sequence their data may have exclusive use arrangements with particular pharma companies
• Family based DNA searching, which came to the fore in solving cold cases, is now being used in active cases.
• The UK’s NHS will offer genetic testing for those with rare disease and cancer, but previously it had said that healthy people could opt in to testing by paying for it. This would have been an anomaly for the NHS, and the plan faced a backlash. It has now been replaced with a plan for 5 million volunteers to get the sequencing for free.

 

Regulation

• How do other countries balance the needs of patients with those of life, insurance, and disability insurers? An international comparison leads the authors to call “for regulatory and industry leadership to come together to establish a voluntary moratorium on insurance pricing with the aim of protecting research participants.”
• The International Commission on the Clinical Use of Human Germline Genome Editing has had its first meeting.
• An argument that germline embryo editing may never be legal in the US, because the rules governing clinical trials require no more than a minimal risk if children are involved unless there is a corresponding benefit to the child. And this can never be met because there is no child.
• The first US law directly relevant to CRISPR has been signed in Calfiornia. It is a consumer protection law that will require gene-editing kits to come with a clear label that they are not for self administration.
• China will have a new National Bioethics committee.
• Japan has approved the first human-animal embryo experiments. The aim is to produce animals with human organs that can then be transplanted into humans.
• An NHGRI project on ELSI genetics issues will be HQed at Stanford, with participation of many other centers. It will collate research and make it available, including tailoring content to different groups.
• A look at the practical and ethical implications of predictive testing for mental conditions argues for the regular assessment of opinions — alongside other parts of the research agenda. I completely agree.

In addition to various news sites (GenomeWeb, STAT) and newsletters (e.g. GA4GH) I usually use Rxvist to see what’s new. They show which pre-prints have been generating the most tweets. Except this month, that functionality is broken, so they’re showing the most downloaded articles instead — many of which were not published recently. The top hits in genetics/genomics include face prediction, tutorial for how to construct polygenic scores, ancestry, the effects of an extra X, and single-cell methods.

The stories that have been grabbing my attention are those that link genetics and identity. An excellent interview  interview with Dorothy Roberts, author of  Fatal Invention: How Science, Politics, and Big Business Re-create Race in the Twenty-First Century, discussed the relationship between genetic ancestry and race. Some selected excerpts

• “Some people think it’s harmless to believe in biological differences between races as long as we don’t value one over another, but the whole point of dividing humans into races is to value some more than others.” 
• “Racism isn’t a product of race. Race is a product of racism. People think it’s OK to categorize people by race as long as they’re not racist, but any division of people into supposedly natural races promotes a racist agenda, whether we intend it to or not.” 
• On the eugenics movement: “If certain groups of people are at a disadvantage, the thinking went, it must be because of their biological inferiority, not due to state violence and structural inequalities…. Such thinking is still used to explain social inequality in the present: If we believe biology produces these unequal social and economic conditions, then how can they be immoral and in need of change? They are “natural.” The situation can’t be changed.” 
• On where you look for explanations: “Have you looked into the fact that black children get expelled and arrested at far higher rates than white children for the same behaviors, like missing school, talking back to a teacher, or roughhousing? Have you looked for any explanations other than within the gray matter of their brains?”” 
• “If you add a new technology to an already racist system, you’ll get another racist product.” 
• And her conclusion: “I don’t believe we should be “color-blind,” that we shouldn’t pay any attention to race. As a political invention, race continues to determine power arrangements and is not going to just go away. We have to dismantle racist institutions to affirm our common humanity. And to do that, we need to understand how the concept of race really functions.” 

An interesting study on what happens when white nationalists find out some of their ancestry is not European. A study looked at the responses individuals in a white nationalist group got when they posted their unexpected results — the vast majority of comments they received focused on potential inaccuracies of the testing. The authors conclude: “White nationalism is not simply an identity community or political movement but should be understood as bricoleurs with genetic knowledge displaying aspects of citizen science.”

Genetic identity is key to the debates over donor conception. In the news recently have been reveals of prior mix-ups in sperm donor conception based on genetic testing. One couple whose children were conceived with a donor they didn’t select is revealing of attitudes within the process: ““I didn’t choose someone who has a history of brain cancer in the family. I would never have chosen this donor. They should be ashamed to even have this donor on the website.”” The position of the courts is that there are no grounds to sue if the child is healthy. Meanwhile a Singaporean court defined a new type of loss, a loss of genetic affinity, to deal with a case of a couple who unintentionally ended up with a bi-racial child.

Science

• A study comparing the results from the SNP chips and the NGS data in the UK Biobank finds that SNP chips are very unreliable for rare variants — for variants <0.001% frequency in the biobank, only 16% confirm with sequencing
• A deep-learning approach to probing the role of non-coding variants in autism.The approach focused on finding potential regulatory consequences of the non-coding variants. They have a nifty website.
• A study across five countries places the heritability of autism at around 80%.
• Most hunts for the variants underlying rare disease look for one or a pair of variants in a single gene. New software for locating pairs of pathogenic variants across two genes. Relatedly, an example of a family whose heart issues stemmed from oligogenic inheritance, in this case the affected children inherited two variants from their father and one from their mother, which, in concert, caused heart issues.
• The benefits of using data beyond individuals with no European Ancestry. Large GWAS on diverse datasets: “Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications.” Example of differences (from the accompanying NIH press release): “a strong association was found between a new genomic variant and smokers and their daily cigarette usage in Native Hawaiian participants. However, this association was absent or rare in most other populations.”
• Polygenic scores for cognitive abilities and educational attainment received a further boost from “multi-trait” analysis. “In a representative UK sample of 7,026 children at ages 12 and 16, we show that we can now predict up to 11% of the variance in intelligence and 16% in educational achievement. We also show that predictive power increases from age 12 to age 16 and that genomic predictions do not differ for girls and boys.”
• A variant in the gene SHARPIN, found only in Japanese individuals, increases the risk of Alzheimer’s 6 fold.
• A massive RNA screen shows just how common somatic variants are, across all tissue types.
• New study on the relevance of the microbiome for athletic performance, pointing to the ability of certain bacteria do metabolize lactate. Watch out, WADA. 
• A study that identifies epigenetic regions that could be used clinically: “At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample.” 
• A nice review of polygenic scores that has a table that compares the relative risk of a disease of those in the top 20% of the score to the bottom 20% of the score

Applications

• Does receiving genetic results affect patients psychologically? A paper from the CSER consortium says No: “Our findings across multiple clinical settings suggest no clinically significant psychological harms from the return of ES/GS results.”
• A review article that argues that the intended use of polygenic scores should guide score development.
• Testing what risk information individuals want to know — mostly when mitigations are possible.
• Helix is pivoting to being a partner in population genomics. It launched to great fanfare as a company selling apps on otp of exome sequencing, which presumably was not going well…
• Education alongside genetic test results is often lacking. Here’s a survey that shows that parents of kids with ASD want to know about the accuracy, cost, and benefits of testing. 
• Genes for Good, a project that uses facebook to engage with research participants, has sequenced over 20,000 individuals. “Health history and daily tracking surveys are administered through a Facebook application, and participants who complete a minimum number of surveys are mailed a saliva sample kit.”
• EMBL-EBI have released software for genome interpretation, using VEP for variant filtration, called gene2phenotype.
• Muin Khoury of the CDC states their approach to polygenic scores: “We think there is a great potential for PRS to make a health impact in certain clinical scenarios, if we can answer three broad questions using a rigorous scientific agenda: 1) Construct scientifically valid PRS within each population ancestry group using relevant variables; 2) For each intended clinical use of PRS (by disease, population, setting), study the added clinical value of the PRS, and overall balance of benefits and harms of PRS in rigorous research studies (including randomized controlled clinical trials or other rigorous hybrid implementation designs); 3) Assess ethical, legal and social issues that result using PRS in different populations, including policy and reimbursement issues, provider and public education as well health system and organizational readiness.”
• An argument from bioethicist Sandra Soo-Jin Lee that the success of precision medicine requires careful thinking about diversity in order to be trusted.
• In an update to the CRISPR babies story, the variant that He Jiankui engineered into lulu and Nana has been associated with earlier death. Meanwhile a russian scientist is planning to edit more embryos-destined-to-be-babies, targeting the same gene. He thinks that his experiment will be ethical because, unlike He, he will only do the engineering if the mother is HIV positive and hence at risk of passing along the infection. The same scientist has announced plans to edit embryos of deaf parents, both of who carry two variants in the GJB2 gene, so that their children can hear. He has five couples lined up. ““The first human trials should start with embryos or infants with nothing to lose, with fatal conditions,” says bioethicist Julian Savulescu of the University of Oxford. “You should not be starting with an embryo which stands to lead a pretty normal life.””
• 23andMe is piloting asking some customers to link their Electronic Health Records – this would include diagnostic reports, lab results, and medical history.
• Nigerian based 54 Gene wants to build a huge biobank of Africans. 
• Veritas has dropped the price of a whole genome from $999 to $599.

Regulation etc

• ICE is planning on expanding its DNA testing on the border — the idea is to identify families who do not share genetic relationships, so that they can be labelled as fraudulent.
• Language in a 2020 US spending bill currently includes a ban on human germline modification (it was dropped for a time based on lack of public engagement on the issue).
• Iran is considering making genetic testing free for those families at risk of having a child with a disability. Last year, they announced that genetic testing could reduce births of those with disorders by 50%. These comments are of course out of line with the more familiar mantra that such testing is done only to enhance reproductive freedom. 
• Genetic genealogy has helped identify many suspects. Now they have helped convict someone. “The defense could have challenged the use of genetic genealogy on privacy grounds, or as a violation of people’s right to control their personal data. Instead, defense lawyers did not pose a single question about the technique.”
• A call from many experts for the legalization of mitochondrial therapy, which is legal in other countries including the UK.

An interview with George Church touching on many future tech possibilities: “Just being different at all from the middle of the bell curve gives you an advantage in a part of society that cherishes innovation and out-of-the-box thinking.” 

I’ve started this round-up with recent papers focused on two scientific themes that will dominate the near term progress in understanding links between genotype and phenotype, 1) trouble ahead for polygenic scores, and 2) the coming together of rare and common variation analysis.

Trouble for polygenic scores

Previous work on the genetics of human height, based on the GIANT consortium, had identified evolutionary adaptation signatures to explain the North-South height gradient. But two new studies applying the same methodology to the more homogenous and larger UK Biobank data found no such evidence. They did find that the same SNPs were identified, and with similar effect sizes. But population structure biases these effect sizes. This is particularly problematic on meta-analysis that combine heterogeneous data sources. And is much worse if sub-significant SNPs are included. This should cause extreme caution when a) looking for signals of polygenic adaptation, b) between-population differences. Additionally, this population structure can be “an additional source of error in polygenic scores and affect their applicability even within populations.” (paper 1). As “even small differences in ancestry will be inadvertently translated into large differences in predicted phenotype” (paper 2). These results are nicely put in context here, with a quote from a former teacher of mine, “The methods developed so far really think about genetics and environment as separate and orthogonal, as independent factors. When in truth, they’re not independent. The environment has had a strong impact on the genetics, and it probably interacts with the genetics,” said Gil McVean, a statistical geneticist at the University of Oxford. “We don’t really do a good job of … understanding [that] interaction.”

Question: what would the same analysis show for the Educational Attainment polygenic score? Which stands as the other score based on very large heterogeneous data, and utilized many non-significant SNPs.

A separate preprint shows how, even within an ancestry group, porting polygenic scores has its challenges. “The prediction accuracy of polygenic scores depends on characteristics such as the age or sex composition of the individuals in which the GWAS and the prediction were conducted, and on the GWAS study design.”

 

Coming together of rare and common variation.

We’re getting to the stage of having very large cohorts of NGS data. What will we learn of how common and rare variation jointly contribute to disease? And what implications does this have for the clinic?

An exome cohort of over 20,000 T2D cases and 24,000 controls, representing one of the largest studies yet using NGS data. For 76% of their cohort they also had array data plus imputation. The broad relevance of this type of study lead me to read this paper fairly closely. What did they find?

• Looking exome wide, of the 6.3 million variants in their data set, 15 were exome-wide significant. They were powered to find variants with an effect size of OR 2.5 at a frequency of 0.2%
• They aggregated to the gene level and found 3 significant genes. Looking at the near misses in other datasets leads them to think that these will become exome wide significant in the future. They estimated that the top 100 gene level signals would capture a mere ~2% of the genetic variance in their sample.
• Then they aggregate another level up, at the gene set level, only drawing the weak conclusion that this line of work “can be used as a potential metric to prioritize candidate genes relevant to T2D.”
• They found almost all the variants they had found in the exome data in the array data (8 of the 10 single variants), and then 14 more non-coding in the array data. The vast majority of their overall variants were not imputable. Because the array data identified common variants, it explained more of the genetic liability
• The basic issue is that they continue to be underpowered to a) find rarer variants (<<0.2%), b) accurately estimate their effect sizes. They suggest, as an antidote to (a), relying on prior suspicions of a gene-disease connection to narrow search space (and hence lower threshold for detecting significance).
• They conclude that for research, GWAS are best for “locus discovery and fine mapping”, and NGS for gene characterization and confidence in gene-disease connections.
• And for personalized medicine, the very rare variants of large effect sizes may be useful, but these are so rare as to complement (rather than replace) polygenic scores based on array data.

 

Science

• Large datasets such as the UK Biobank are showing that a lot of the candidate gene work was spurious. Here is a piece from Ed Yong focusing on SCL6A4 and its connections with depression, which about 450 papers investigated. Now many are claiming that there is no evidence that the connection exists (and indeed that this has been clear for years now). But some are saying that we know the effects of this gene depend on the environment, and the new studies do not measure the environment anywhere near as accurately as needed.
• Sarah Zhang at the Atlantic points out another enduring legacy of some of the candidate gene work. A gene called MTHFR was associated to adverse results following smallpox vaccination in a small 2008 study. Just like other candidate genes, it hasn’t stood the test of time. But MTHFR is the single gene that 23andMe gets the most questions about, by Anti-Vaxxers hoping to find their child has a variant that will get them a medical exemption from vaccination (to do this they have to download their raw data and upload it somewhere else).
• In a preprint Plomin et al argue on the basis of ~7000 twin pairs for the existence of a substantially heritable (50-60%) p-factor, polygenic general psychopathology factor
• A study in PNAS and a write-up in the NY Times locates several more cases where an extreme difference in smell perception can be linked to single SNPs.
• A polygenic score for obesity, with those in the top decile 13kg heavier than those in the bottom decile by age 18.
• A large (~30k cases, ~170k controls) GWAS of bipolar disorder identifies 30 genome wide significant variants. One scary thing: their first analysis was of a subset of the data (20k cases, 31k controls), in which they found 19 variants, 8 of which did not replicate in the combined analysis.
• Most people who are at a 50% risk of developing Huntingtons disease do not want to know if they carry the genetic variant. Why? A study based on data from 1999-2008 found the two biggest reasons were no effective cure/treatment (66%) and inability to undo knowledge (66%).

 

Applications

• DNA testing of genetic parent-child relationships has started at the US-Mexico border. The claim is that some children are “recycled” to help get adults into the US, though there is no evidence that this happening on any scale. The technology is the same used police to see if a suspect’s DNA has a database match.
• GEDmatch, the main source of genetic data used by the police, has changed its policy such that people have to opt in to this use.
• A new start-up, Verve therapeutics, aims to simultaneously edit many variants affecting heart disease. They’ve nabbed Sekar Kathiresan, who has published some of the most significant polygenic scores, as their CEO.
• An ambitious $1.7bn Russian government push for gene edited plants and animals.
• 23andMe and AirBnB have teamed up for travel bookings connecting people with their heritage. The press release shows that “heritage travel” is indeed a large market, and they have some quirky stats to go with it, e.g. “57% of survey respondents in the United States would give up alcohol for a year for a free heritage trip”.
• Ancestry.com have continued to stir controversies about the links between identity and DNA. They just pulled an advert that showed a white man trying to entice a black woman to leave the South during the pre-civil war era with an engagement ring.

 

Regulation

• The National Academies and The Royal Society are spearheading an International Commision to investigate appropriate use of human germline editing. They are set to report in Spring 2020.
• A German ethics council has expressed that there is nothing intrinsically wrong with germline modification, but that we’re not there yet. This non hardline approach is particularly significant coming from Germany. Due to the history of eugenic Nazi practices, it is usually the most conservative when it comes to any reproductive technology that could influence which children are born.
• China is rewriting its civil code, and a section has been added that would make those who carried out the editing of embryos or adults responsible for any negative effects. This is in addition to draft regulations that would impose an approval process on those who wanted to modify embryos.
• The LawSeq project is wrapping up and a couple of good articles have used that as an excuse to cover the legal state of play when it comes to genomics. One, in Science, covers medical malpractice cases involving genetics, showing that plaintiffs have a much higher success rate in this than in other areas of medicine. An example is of a family who successfully sued a doctor who treated a man who died of a heart condition for not not recommending that they get their son genetically tested. The doctor never treated the son, who also died. The other, in Wired, focuses on the shortcomings of the patchwork of laws that cover genetic privacy.
• A contestant on the Bachelorette’s claims to have 114 children as a sperm donor has highlighted issues with the field of donor conception, specifically its lack of regulation. Other countries limit the number of children per donor, but there are only vague, non-binding guidelines in the US. The main fears are of accidental incest between siblings, cases where the donor has a genetic disease that only shows up later in life, and unknown psychological impacts on children on having that many siblings.
• Controversial biohacker Josiah Zayner, famous for self-injecting a DIY gene therapy has been called to interview for suspected unlawful practice of medicine by the California Department of Consumer Affairs.
• (Not really regulation) An an Op-Ed in the Daily News, Kathryn Paige Harden says we need to accept the genetics that helps us get ahead in life as a form of privilege, and that refusing to do so “feeds the myth” that America is a meritocracy.

The issues are somewhat clearly identified. The lack of concrete proposals is deafening.

 

Yesterday I attended an event at Harvard, “Editorial Humility: A Moratorium on Human Germline Editing?”, sparked by the recently published call for a moratorium on human germline editing that Eric Lander co-authored with 17 others.

Back in 2015 there was a clear call for a moratorium, with a focus on whether this is a road we want to go down at all. In 2017, the National Academies of Science and Medicine published a report that watered down this call, focusing on questions of safety and efficacy (I argued at the time against this watering down). He Jiankui pointed to this NASAM report in claiming that there was no clear writ against his decision to pursue the human germline editing that lead to the birth of Lulu and Nana. In other words, the absence of a clearly called for moratorium likely had a role in the actual use of the technology.

Is a moratorium the right approach? Eric Lander, speaking first, explained that the main aim of the new call was to seed the debate. He is backed by the NIH, represented at the event by Carrie Wolinetz. In the US there is a ban against germline editing already in place, but the world’s largest funder of biomedical research nonetheless thought using their “bully pulpit” position in support of a moratorium was the right thing to do.

A moratorium is a lightweight solution. It would be time limited from the get go. And it would leave eventual decisions with each sovereign power on a country by country basis. For panellists Betsy Bartholet and Sheila Jasanoff, this does not go far enough, and we should be aspiring to an International Treaty. Betsy Bartholet called on Eric Lander and the concerned scientific community to start the work to get a treaty in place. Eric Lander called on Bartholet and the lawyers to instead do this work. Both claimed a lack of expertise. This was concerning. An example of how things can truly fall between the cracks.

Playing devil’s advocate, I Glenn Cohen argued that moratoriums can be “sticky”, even if they have a sunset clause. Moreover, bioethicists have been talking about this for years; we’ve done all the thinking we need to. He also argued that we need to de-exceptionalize genetic modification as a technology. Many technologies, e.g. smartphones, have disturbing ethical implications. I agree with Lander’s response that Yes, we have issues across the board when it comes to new technologies, but that’s a reason to engage with all of them, not to disengage with this one.

Steve Hyman, ex-provost of Harvard, said that he was much more concerned about the use of cognitive polygenic scores for selecting embryos. Given my research interests, no surprise that I strongly agree. I’ve also published (joint with Sarah Polcz) that although scientists are making a big distinction between heritable/non-heritable, I think the bigger distinction is therapy/enhancement.  

I took two main things away from the panel.

First, everybody was horrified that the scientific community so thoroughly dropped the ball. Many others knew what He Jiankui was up to, and no-one raised the alarm. (Note that the scientific community is divided about whether blame should fall entirely on He or not.) What should be done? Eric Lander made the case that you can’t expect scientists to self-regulate because they have an inherent conflict of interest. When you work on anything you have to be the biggest believers in the upsides, the optimists. Jasanoff reminded Lander that the metro between Harvard and Kendall “runs both ways”, and that he should come to the Kennedy School more often to explore the issues from a different point of view. The question of the role of scientists seems prescient in light of the debate over the extent to which the social media giants can and should self-regulate. In this arena, bioethicists are given heat for being too conservative, for overplaying the risks of a technology and failing to see the potential benefits. So what is the right balance of roles?   

Second, as ever, there were broad calls for public debate. But when it came to concrete proposals for “deliberative explorations”, nothing. There was reference to learning about how other countries have done this. The UK is always held up as the shining example. (And the inevitable “How do they manage to achieve consensus on the use of reproductive technologies, but end up in such a mess over Brexit?”). I’ve added to my To Do list a comparative approach to the various approaches to public engagement taken around the world with respect to mitochondrial replacement therapy. Approaches that have caught my eye include the Moral Machines work, where the public were invited to state who they thought a self-driving car could kill. And something like what the folks at World Wide Views are up to. I’m very interested to hear of deliberation and public engagement that others are enthusiastic about.

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.

Two truly ginormous releases of data

• The Biobank, ~500,000 individuals with extensive phenotypes, has released the first ~50,000 whole exome sequences (complementing the Chip data that has been around for longer).
• The National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program has a data set of ~50,000 whole genomes (of a planned 145,000). An exciting fact about this data set is that ~30% are from individuals with African ancestry. The individuals are extensively phenotyped. Much of the genetic data (I’m unclear how much) is available on dbGap.

The size of NGS data has truly exploded. Here’s hoping that this sort of size dataset will allow us to peel back the curtain on the clinical relevance of rare variation.

Controversy — mostly China

• More on CRISPRed babies
  • Inadvertent cognitive enhancement? – The edit introduced into the CCR5 gene in Lulu and Nana is associated with increased smartness in mice, and faster recovery from stroke and higher school success in humans.
  • In further twists, perhaps state agencies in China knew more than they were letting on about He’s experiments, which are now very much being portrayed as those of a “rogue actor”
  • Approval of future trials involving gene-editing would be handled by China’s national cabinet, the State Council, under new proposals by Beijing to further regulate gene-editing.
• The Times covers the story of Beijing’s genetic surveillance of the Uighur population. Thermo Fisher, whose instruments and expertise have been used as part of the program,  have stopped sales and services of instruments to be used in Xinjiang province, stating conflict with their ethics code. Bioethicist Dr Caplan was quoted as saying “Honestly, there’s been a kind of naïveté on the part of American scientists presuming that other people will follow the same rules and standards wherever they come from.”
• “Talent testing” for toddlers is a thing in China, e.g. CBT Gene in Shenzhen, whose genetic tests cover  “musical, mathematical, and reading abilities; physical talents; attributes like shyness, introversion, extroversion, and memory.”

Science

• A massive GWAS for depression covering 100,000s of cases and controls has identified new loci. The resulting polygenic score explained 1.5-3.2% of the variance (for a condition with an estimated heritability of 30-40%), depending on target cohort.
• The Human Reference Genome is increasingly under attack. Its problems have been obvious for a long time, but attention is now starting to really focus on them. See this piece giving the historical context from STAT. And a recent paper probing structural variant that really highlights the issue — they found 60MB of sequence not mappable to the reference genome.
• Some conditions affect different ancestral populations to different degrees. Asthma affects those of African ancestry disproportionately, but has been understudied in that population. A new study looking at African-admixed asthma cases and controls identifies “two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.”
• An impressive new technology for looking at genome wide gene expression levels at high spatial resolution, Slide-seq.
• A report on the heritability of child maltreatment; “our findings suggest that genetic pathways play a significant role in perpetrating emotional abuse, while physical abuse and emotional neglect are transmitted primarily through common environmental factors.”
• A gain of function variant in the gene LRRK2 is known to significantly increase the chances of an individual developing Parkinsons. Could inhibition of the same gene be therapeutic? The authors looked in large data sets (GnomAD and 23andMe) to find individuals who had only one working copy of the gene, and found no ill effects, suggesting that inhibition could indeed be a safe strategy to pursue.
• We’re used to seeing mitochondrial DNA represented as small circles, but new long read data shows that this is an oversimplification: “Our data demonstrate that representations of plant mitochondrial DNA as simple, genome-sized circular molecules are not accurate descriptions of their true nature and that in reality plant mitochondrial DNA is a complex, dynamic mixture of forms.”
• Dealing with the effects of variants on multiple transcripts has always been a problem for genome annotation. Here is a new tool from the GnomAD team that will do expression based annotation (it takes an isoform expression file as an input).

Applications

• 23andMe have launched a Type 2 Diabetes score. Using a freshly developed polygenic score based on their 2.5 million customers, it adjusts the score based on ethnicity and age to give not just a relative odds, but a percentage chance of developing the condition in the next x years. I was unable to confirm this as it doesn’t work on my report — perhaps because it only works for the latest chip.
• The PeopleSeq consortium has partnered with the major projects that offer genome sequencing to healthy individuals (“predispositional screening”). They send out surveys to participants before and after screening. In their first published results covering several hundred people, they found that while most individuals discussed the results with their doctor, only 13.5% made an appointment specifically for that purpose. About 40% reported that they learnt something new about their health, but fewer than 10% made any changes. More than half were disappointed that they did not receive more actionable information. One message the authors want us to take home: patients felt empowered rather than distressed by their results.
• A group of 8 institutions wants to see whole genome sequencing in the clinic, and have formed the Medical Genome Initiative to help establish best practices etc to make this happen.

Regulation

• Following the case of the rape (and subsequent pregnancy) of a woman in an intermediate care facility, Arizona is considering a law to make it mandatory for people who work with the intellectually disabled in these facilities to provide DNA samples first. This is a watered down version of the proposal that started with mandating that anybody who had to be fingerprinted as part of their work would have to give a sample.
• Meanwhile, Kansas are considering a bill that will see new DNA samples matched to not just open cases but also closed cases. This would help in cases where the wrong person was convicted for a crime.
• A family’s story that highlights the difficulties with anonymous sperm donors

And in other interesting things, here is a nice write-up of the extent to which humans are innately violent — tracing the debates, and pointing to the question, do we need an answer to this question? Also, whether our views on this question affect our beliefs about peace-keeping efforts.

Controversy

• An opinion piece in STAT by Michael Joyner and Nigel Paneth against the genetic reductionism of precision medicine: “We are calling for an open debate, in all centers of biomedical research, about the best way forward, and about whether precision medicine is really the most promising avenue for progress. It is time for precision medicine supporters to engage in debate — to go beyond asserting the truism that all individuals are unique, and that the increase in the volume of health data and measurements combined with the decline in the cost of studying the genome constitute sufficient argument for the adoption of the precision medicine program.” Their piece references a 1999 lecture from Francis Collins. He explains the background to the Human Genome Project (“a public science initiative focused so sharply on the molecular essence of humankind was too intriguing and too promising to forgo”) and then lays out his vision for what we now call Personalized Medicine, including an imagined 2010 encounter where a young soker learns of his increased risk of lung cancer, which “provides the key motivation for him to join a support group of persons at genetically high risk for serious complications of smoking, and he successfully kicks the habit.”

Science

• Race as a biological variable. A paper that finds differences in Alzheimer biomarkers between African-Americans and non-Hispanic whites: lower cerebrospinal fluid concentrations of tau, with results varying by APOE status. In addition to a race-by-biomarker interaction, this is a race-by-genotype interaction. They argue that these uncovered links mean that a) any attempts to use biomarkers in diagnosis should adjust for race, and b) hope for better treatment based on incorporating “race dependent biological mechanisms”.
• A review of polygenic risk scores in psychiatry. Reviews use of GWAS for “increasingly informative individual-level genetic risk prediction” for psychiatric disorders, which are not yet ready for the clinic. Does a nice job of showing that the idea of summing up the effects of many genetic variants to explain a continuous phenotype goes back to the very beginning of the study of hereditary. “ To understand how to incorporate PRS into clinical practice for patients with heritable psychiatric disorders, studies will need to assess health outcomes for various behavioral interventions, treatment regimens, and/or differential diagnoses” They make an interesting observation as regards height: “prediction accuracy is not distributed evenly; it performs particularly poorly at the extreme short end of the height distribution, indicating a larger contribution of environmental factors, large-effect rare variants, and/or other factors in these individuals”
• Polygenic scores are trained on cohorts of diagnosed individuals. A Danish study shows that polygenic scores for depression are also predictive in a general cohort. A score of one standard deviation above the mean gives a 30% increased chance of a diagnosis of depression.

Applications

• A look at how consumer genetic testing companies market testing for Native American ancestry, focusing on the claimed links to identity. They wonder, whilst acknowledging it is beyond the scope of their paper, “Are companies changing consumer behavior, or are consumers already coming in with certain expectations of verifying tribal ancestry and using the results as a means to accomplish this goal?” (See this paper for qualitative interviews with 100 people looking at this question). The paper references that the US government required tribes in 1934 to have a minimum “blood quantum” for enrollment. There is clear, and problematic, precedent for the use of genetics/blood to define identities. Rewind the clock to 2013, and in giving the majority opinion against a Native American father in a complicated court case, Justice Alito choose to start with “This case is about a little girl (Baby Girl) who is classified as an Indian because she is 1.2% (3/256) Cherokee.”, seemingly drawing attention to the genetic component of her Indian-ness, and in particular that it was only 1.2% (I recommend the More Perfect podcast episode about this case). Reading more about these considerations convinces me of just how counterproductive it was for Elizabeth Warren to act upon Trump’s goad to be genetically tested to proof her claims of Native ancestry.
• A piece on SpectrumNews, about the benefits of genetic testing. I was struck by this quote from the mother of a child who received a pathogenic finding when her daughter was an adolescent: “Instead of trying to change her behaviors, we’re modifying how we take care of her… It has given me a lot of relief knowing where her autism comes from, and that there was nothing I could have done differently.” Her daughter was the “way she is because of biology”. Routine genetic testing, if it had been available at the time could have saved her ”years of worry and guilt”.  
• Antonio Regalado reports on a start-up working towards designer babies. One of the founders “is skeptical of the role regulations can play—a lesson he says he learned working with Bitcoin, a digital currency outside the control of any central bank.” I was alarmed at this: “Bishop told me none of the ethicists he e-mailed had ever gotten back to him.”
• The FBI can now send a sample to FamilyTree, and they will sequence it and see if it matches anything in their database:
• Speaking of polygenic scores, did you see that the Scripps has an App for that?
• Some lovely visual explainers of the difference between NGS and genotyping from NYT.

Regulation/Ethics

• Designing babies with high IQs may be far off, but selecting between embryos based on polygenic scores for IQ is more or less upon us (witness Genomic Prediction). Erik Parens, Paul Appelbaum, and Wendy Chung argue that profiling embryos for IQ would be unethical. Parents have two competing ethical obligations: to accept their children as they are, and to shape their children. The market is producing a “grotesque” pull towards the latter. “Placing limits on the genetic selection of embryos is one small way for our society to affirm the importance of achieving a balance between the ethical obligations to shape our children and to accept them as they are — and the importance of closing, rather than widening, the gap between the rich and the poor.” They argue for regulation, pointing out that the UK manages to do just that.
• Ethics dumping? The Economist asks whether Deem — the American scientist who was He’s thesis advisor and who had same role in the notorious experiments — is guilty.

The Backstreet Boys have a new album called DNA. Why? Watch this cringeworthy explainer.