This is a guest post by Danny Wilson from the University of Oxford. Danny was recently awarded a Wellcome Trust/Royal Society fellowship at the Nuffield Department of Medicine, and in this post he tells us why you cannot understand human genetics without studying the genetics of microbes. If you are a geneticist who finds this post interesting, he is currently hiring.
Never mind about sequencing your own genome. Only 10% of cells on your “human” body are human anyway, the rest are microbial. And their genomes are far more interesting.
For one thing, there’s a whole ecosystem out there, made up of many species. Typically a person harbours 1,000 or more different species in their gut alone. For another, a person’s health is to a large part determined by the microbes that live on their body, whether that be as part of a long-term commensal relationship or an acute pathogenic interaction.
With 20% of the world’s deaths still attributable to infectious disease, the re-emergence of ancient pathogens driven by ever-increasing antibiotic resistance, and the UK’s 100K Genome Project– many of which will have to be genomes from patients (i.e. microbes) rather than patients’ own genomes given its budget – pathogen genomics is very much at the top of the agenda.
So what do pathogen genomes have to tell us? Continue reading ‘Guest post: Human genetics is microbial genomics’
This guest post from Daniel Howrigan, Benjamin Neale, Elise Robinson, Patrick Sullivan, Peter Visscher, Naomi Wray and Jian Yang (see biographies at end of post) describes their recent rebuttal of a paper claiming to have developed a new approach to genetic prediction of autism. This story has also been covered by Ed Yong and Emily Willingham. Genomes Unzipped authors Luke Jostins, Jeff Barrett and Daniel MacArthur were also involved in the rebuttal.
Last year, in a paper published in Molecular Psychiatry, Stan Skafidas and colleagues made a remarkable claim: a simple genetic test could be used to predict autism risk from birth. The degree of genetic predictive power suggested by the paper was unprecedented for a common disease, let alone for a disease as complex and poorly understood as autism. However, instead of representing a revolution in autism research, many scientists felt that the paper illustrated the pitfalls of pursuing genetic risk prediction. After nearly a year of study, two papers have shown how the Skafidas et al. study demonstrates the dangers of poor experimental design and biases due to important confounders.
The story in a nutshell: the Skafidas paper proposes a method for generating a genetic risk score for autism spectrum disorder (ASD) based on a small number of SNPs. The method is fairly straightforward – analyze genetic data from ASD case samples and from publicly available controls to develop, test, and validate a prediction algorithm for ASD. The stated result – Skafidas et al. claim successful prediction of ASD based on a subset of 237 SNPs. For the downstream consumer, the application is simple – have your doctor take a saliva sample from your newborn baby, send in the sample to get genotyped, and get a probability of your child developing ASD. It would be easy to test fetuses and for prospective parents to consider abortions if the algorithm suggested high risk of ASD.
The apparent simplicity is refreshing and, from the lay perspective, the result will resonate above all the technical jargon of multiple-testing correction, linkage disequilibrium (LD), or population stratification that dominates our field. This is what makes this paper all the more dangerous, because lurking beneath the appealing results is flawed methodology and design as we describe below.
We begin our critique with the abstract from Skafidas et al. (emphasis added):
Continue reading ‘Guest post: the perils of genetic risk prediction in autism’
Barbara Prainsack is at the Department of Social Science, Health & Medicine at King’s College London. Her work focuses on the social, regulatory and ethical aspects of genetic science and medicine.
More than seven years ago, my colleague Gil Siegal and I wrote a paper about pre-marital genetic compatibility testing in strictly orthodox Jewish communities. We argued that by not disclosing genetic results at the level of individuals but exclusively in terms of the genetic compatibility of the couple, this practice gave rise to a notion of “genetic couplehood”, conceptualizing genetic risk as a matter of genetic jointness. We also argued that this particular method of genetic testing worked well for strictly orthodox communities but that “genetic couplehood” was unlikely to go mainstream.
Then, last month, a US patent awarded to 23andMe – which triggered heated debates in public and academic media (see here, here, here, here and here, for instance) – seemed to prove this wrong. The most controversially discussed part of the patent was a claim to a method for gamete donor selection that could enable clients of fertility clinics a say in what traits their future offspring was likely to have. The fact that these “traits” include genetic predispositions to diseases, but also to personality or physical and aesthetic characteristics, unleashed fears that a Gattaca-style eugenicist future is in the making. Critics have also suggested that the consideration of the moral content of the innovation could or should have stopped the US Patent and Trademark Office from awarding the patent.
Continue reading ‘Guest post: 23andMe’s “designer baby” patent: When corporate governance and open science collide’
Dr. Tuuli Lappalainen is a postdoctoral researcher at Stanford University, where she works on functional genetic variation in human populations and specializes in population-scale RNA-sequencing. She kindly agreed to write a guest post on her recent publication in Nature, “Uncovering functional variation in humans by genome and transcriptome sequencing”, which describes work done while she was at the University of Geneva. -DM
In a paper published online today in Nature we describe results of the largest RNA-sequencing study of multiple human populations to date, and provide a comprehensive map of how genetic variation affects the transcriptome. This was achieved by RNA-sequencing of individuals that are part of the 1000 Genomes sample set, thus adding a functional dimension to the most important catalogue of human genomes. In this blog post, I will discuss how our findings shed light on genetic associations to disease.
As genome-wide studies are providing an increasingly comprehensive catalog of genetic variants that predispose to various diseases, we are faced with a huge challenge: what do these variants actually do in the cell? Understanding the biological mechanisms underlying diseases is essential to develop interventions, but traditional molecular biology follow-up is not really feasible for the thousands of discovered GWAS loci. Thus, we need high-throughput approaches for measuring genetic effects at the cellular level, which is an intermediate between the genome and the disease. The cellular trait most amenable for such analysis is the transcriptome, which we can now measure reliably and robustly by RNA-sequencing (as shown by our companion paper in Nature Biotechnology).
In this project, several European institutes of the Geuvadis Consortium sequenced mRNA and small RNA from lymphoblast cell lines from 465 individuals that are in the 1000 Genomes sample set. The idea of gene expression analysis of genetic reference samples is not new (see e.g. papers by Stranger et al., Pickrell et al. and Montgomery et al.), but the bigger scale and better quality enables discovery of exciting new biology.
Continue reading ‘Uncovering functional variation in humans by genome and transcriptome sequencing’
This is a guest post by Graham Coop and Peter Ralph, cross-posted from the Coop Lab website.
We’ve been addressing some of the FAQs on topics arising from our paper on the geography of recent genetic genealogy in Europe (PLOS Biology). We wanted to write one on shared genetic material in personal genomics data but it got a little long, and so we are posting it as its own blog post.
Personal genomics companies that type SNPs genome-wide can identify blocks of shared genetic material between people in their databases, offering the chance to identify distant relatives. Finding a connection to someone else who is an unknown relative is exciting, whether you do this through your family tree or through personal genomics (we’ve both pored over our 23&me results a bunch). However, given the fact that nearly everyone in Europe is related to nearly everyone else over the past 1000 years (see our recent paper and FAQs), and likely everyone in the world is related over the past ~3000 years, how should you interpret that genetic connection?
Continue reading ‘Identification of genomic regions shared between distant relatives’
Guest Co-Author: Dr Anna Middleton is an Ethics Researcher and Registered Genetic Counsellor, based at the Wellcome Trust Sanger Institute, UK.
The American College of Medical Genetics (ACMG) has recently published recommendations for reporting incidental findings (IFs) in clinical exome and genome sequencing. These advocate actively searching for a set of specific IFs unrelated to the condition under study. For example, a two year old child may have her (and her parents’) exome sequenced to explore a diagnosis for intellectual disability and at the same time will be tested for a series of cancer and cardiac genetic variants. The ACMG feel it is unethical not to look for a series of incidental conditions while the genome is being interrogated, conditions that the patient or their family may be able to take steps to prevent. This flies in the face of multiple International guidelines that advise against testing children for adult onset conditions. The ACMG justify this as “a fiduciary duty to prevent harm by warning patients and their families”. They conclude that “this principle supersedes concerns about autonomy”, i.e. the duty of the clinician to perform opportunistic screening outweighs the patients right not to know about other genetic conditions and their right to be able to make autonomous decisions about testing.
Continue reading ‘No choice for you’
This is a guest post by Peter Cheng and Eliana Hechter from the University of California, Berkeley.
Suppose that you’ve had your DNA genotyped by 23andMe or some other DTC genetic testing company. Then an article shows up in your morning newspaper or journal (like this one) and suddenly there’s an additional variant you want to know about. You check your raw genotypes file to see if the variant is present on the chip, but it isn’t! So what next? [Note: the most recent 23andMe chip does include this variant, although older versions of their chip do not.]
Genotype imputation is a process used for predicting, or “imputing”, genotypes that are not assayed by a genotyping chip. The process compares the genotyped data from a chip (e.g. your 23andMe results) with a reference panel of genomes (supplied by big genome projects like the 1000 Genomes or HapMap projects) in order to make predictions about variants that aren’t on the chip. If you want a technical review of imputation (and the program IMPUTE in particular), we recommend Marchini & Howie’s 2010 Nature Reviews Genetics article. However, the following figure provides an intuitive understanding of the process.
Continue reading ‘Learning more from your 23andMe results with Imputation’
Following the Genomes Unzipped post entitled “Exaggerations and errors in the promotion of genetic ancestry testing”, we received a request to reply from Jim Wilson. Jim Wilson is the chief scientist of BritainsDNA. He is not the one who gave the BBC interview that prompted the Genomes Unzipped post but he is a key contributor to the science behind BritainsDNA. We are keen to tell both sides of this story and this post is an opportunity for BritainsDNA to state their arguments and motivation. -VP
I saw Vincent Plagnol’s post here on Genomes Unzipped about the promotion of genetic ancestry testing and felt compelled to respond. While I did not give the interview that was the subject of the post, I am the chief scientist at BritainsDNA and I feel that the post was biased in presenting only one side of the story and thus misrepresenting the situation. Perhaps I can offer another perspective for readers.
Continue reading ‘Response to “Exaggerations and errors in the promotion of genetic ancestry testing”’
Jimmy Cheng-Ho Lin, MD, PhD, MHS is the Founder/President of Rare Genomics Institute, helping patients with rare diseases design, source, and fund personalized genomics projects. He is also on the faculty in the Pathology and Genetics Departments at the Washington University in St. Louis, as part of the Genomics and Pathology Services. Prior to this, he completed his training with Bert Vogelstein and Victor Veculescu at Johns Hopkins and Mark Gerstein at Yale, and led the computational analysis of some of the first exome sequencing projects in any disease, including breast, colorectal, glioblastoma, and pancreatic cancers.
At Rare Genomics Institute (RGI), we have a dream: that one day any parent or community can help access and fund the latest technology for their child with any disease. While nonprofits and foundations exist for many diseases, the vast majority of the 7,000 rare diseases do not have the scientific and philanthropic infrastructure to help. Many parents fight heroically on behalf of their children, and some of them have even become the driving force for research. At RGI, we are inspired by such parents and feel that if we can help provide the right tools and partnerships, extraordinary things can be achieved.
We start by helping parents connect with the right researchers and clinicians. Then, we provide mechanisms for them to fundraise. Finally, we try to guide them through the science that hopefully result in a better life for their child or for future children. Throughout the whole process, we try to educate, support, and walk alongside families undergoing this long journey.
Continue reading ‘Guest Post: Jimmy Lin on community-funded rare disease genomics’
This is a guest post by Teresa Finlay. Teresa is a PhD student at Cesagen, Cardiff University, studying with Adam Hedgecoe and Michael Arribas-Ayllon. A background in cancer nursing and a degree in human biology informed Teresa’s interest in the public’s use of direct-to-consumer genetic testing to ‘self-screen’ for disease risk. She recently secured funding from the ESRC to research users’ and genetics clinicians’ experiences of DTCGT in the UK. If you are a UK resident who has used a DTC genetic test, or a clinician whose patients have used these tests, then you too can get involved in the research.
Direct-to-consumer genetic testing (DTCGT) has been freely available on the Internet for more than five years, despite concerns from the professional community. Companies marketing these tests (such as 23andMe and deCODEme) claim they are empowering people to make healthy lifestyle choices, and frequently draw on the principle of autonomy as a central argument. This position is confirmed elsewhere by those who view genomic knowledge as an individual right, including many of the bloggers at Genomes Unzipped. Other scientists and clinicians express skepticism about the clinical validity and utility of DTCGT, and raise concerns about the potential for anxiety and inappropriate testing. These debates highlight the importance of research into the motivations and actions of DTCGC customers, but research to date remains very limited, and has mostly been performed on customers in North America. The UK, with its large state-run National Health Service and relative lack of private health insurance and providers, is likely to face unique challenges and situations as DTCGT becomes more common. The paucity of research on UK customers indicates the need for a detailed UK study examining users’ and clinicians’ perspectives in order to establish the long-term implications of DTCGT. This post outlines what is currently known about DTCGT, fills some gaps in the UK context and outlines a research project involving users and clinicians in the UK.
Continue reading ‘UK Users’ and Genetics Clinicians’ experiences of direct-to-consumer genetic testing (DTCGT)’