Author Archive for Katherine Morley

Review of the Lumigenix “Comprehensive” personal genome service

This is the first of a new format on Genomes Unzipped: as we acquire tests from more companies, or get data from others who have been tested, we’ll post reviews of those tests here. The aim of this series is to help potential genetic testing customers to make an informed decision about the products on the market. We’re still tweaking the format, so if you have any suggestions regarding additional analyses or areas that should be covered in more detail, let us know in the comments.


Lumigenix is a relative newcomer to the personal genomics scene: the Australian-based company launched back in March this year, offering a SNP chip-based genotyping service similar in concept to those provided by 23andMe, deCODEme and Navigenics.

The company kindly provided Genomes Unzipped with 12 free “Comprehensive” kits, which provide genotypes at over 700,000 positions in the genome, to enable us to review their product. We note that the company offers several other services, including a lower-priced “Introductory” test that covers fewer SNPs, and whole-genome sequencing for the more ambitious personal genomics enthusiast. This review should be regarded as entirely specific to the Comprehensive test.
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Ethics and Genomic Research: ‘Genomethics’

Dr Anna Middleton is an Ethics Researcher and Registered Genetic Counsellor, based at the Wellcome Trust Sanger Institute. She leads the ethics component of the Deciphering Developmental Disorders study, a collaborative project involving WTSI and the 23 National Health Service Regional Clinical Genetics Services in the UK. This project involves searching for the genetic cause of developmental disorders, using array-CGH, SNP genotyping and exome sequencing, in ~12,000 children in the UK who currently have no genetic diagnosis.

One of the issues raised by this, and many other research projects, is what should happen to ‘incidental’ findings, i.e. potentially interesting results from genomic analyses that are not directly related to the condition under study.  Here Anna discusses the research she is conducting on this topic as part of the DDD study, and provides a link to the DDD Genomethics survey where you can share your own views (I should also disclose here that both Caroline and I also work on the DDD study).[KIM]

Whole genome studies have the ability to produce enormous volumes of valuable data for individuals who take part in research. However, as a consequence of analysing all 20,000+ genes, whole genome studies unavoidably involve the discovery of health related information that may have actual clinical significance for the research participant.  Some of this will be considered a ‘pertinent finding’, i.e. directly related to the phenotype under study (e.g. the child’s developmental disorder); some of this will be considered an ‘incidental or secondary finding’ in that it is not directly linked to the phenotype under study or the research question that the genomic researchers are trying to answer.

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‘Disguised’ heritability, changes ahead to marketing of personal genomics, deciphering developmental disorders

Even though genome-wide association studies (GWAS) have identified many loci associated with complex disease, much disease heritability is still unexplained, or “missing”. But what if rather than being missing, some of the heritability was “disguised”. This is the term put forward by Chris Spencer and collegues to describe the proportion of heritability that we miss because SNPs (imperfectly) correlated to the causal variant (“tag SNPs”) are used to estimate explained heritability rather than causal variants themselves. Reassuringly, their simulations show that for the vast majority of loci detected via GWAS the risk estimated from the best tag SNP is very close to the truth. They also show that, occasionally, fine mapping of GWAS loci will identify causal variants with considerably higher risk and this is more likely if the true effect of the locus is large. The figure above, taken from their paper, shows that for estimated relative risks in the range 1.2–1.3, there is approximately a 38% chance that the true relative risk exceeds 1.4 and a 10% chance that it is over 2. The consequence of all of this for personal genomics is that disease risk could be much greater than currently thought for those individuals who, for a given disease, carry a large number of common risk variants. [CAA]

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People Have A Right To Access Their Own Genetic Information

This week has seen another FDA meeting seeking guidance on how to regulate direct-to-consumer (DTC) genetic tests in the US. The meeting itself has been covered by GNZ bloggers Daniel at Genetic Future and Dan at Genomics Law Report, and its apparent outcome has sparked furious debate elsewhere. The discussion among the “independent” panel convened at the meeting appeared to converge on the proposal that all health-related genomic tests should be ordered and reported through physicians. However, the outcomes of the meeting in terms of FDA policy remain unclear, and one FDA official has indicated that decisions about the availability of genetic tests will be made on a test-by-test basis.

There is no doubt that the appropriate regulation of personal genomics tests is a complex issue, and there is a diversity of opinion about how best to achieve it within GNZ (as there is throughout the genomics community). However, there are several points we agree on:

  • Individuals have a fundamental right to access information about themselves, including genetic information. While it is important to also consider the accuracy, interpretation, validity and utility of tests, this underlying principle should guide policy.
  • There is currently no evidence that DTC genetic tests pose a danger to consumers. A recent study of over 2,000 participants in DTC testing concluded that “testing did not result in any measurable short-term changes in psychological health”. In the absence of any evidence of harm there is no justification for restricting individual autonomy.
  • DNA does not have magical powers, and does not require special treatment simply by virtue of being DNA. Genetic exceptionalism – the idea that genetics must be treated as special under the law – is an inappropriate basis for policy-making. Tests should be regulated appropriately based on their predictive power, utility and potential for harm, all of which are related concepts.
  • As DNA sequencing becomes cheaper, the line between medical and non-medical testing will continue to blur. Excessive regulation of health-related genetic tests could also unncessarily hinder the ability of people to access their entire genome sequences for other purposes (such as genetic genealogy).
  • Most clinicians do not have the appropriate knowledge to interpret genomic tests, particularly in healthy individuals. This point is almost universally agreed, even by the FDA, and has certainly been the experience of some of the GNZ members upon taking our genetic results to doctors. Physicians in general are therefore a strange choice for ‘guardians of the genome’.
  • Most early adopters of DTC genetic tests are sufficiently well-informed to understand the implications of a genomic test and interpret the results correctly. Putting a general physician between these informed individuals and their own genomes is paternalistic and unnecessary.

While the outcome of the FDA’s deliberations remain uncertain, it is clear that there will be intensive lobbying against any attempt at excessive legislation. In the worst case scenario, the fledgling and innovative personal genomics market could be crushed by the FDA. However, there is still plenty of room for a measured approach that enforces test accuracy, punishes false claims and promotes informed choices by consumers, without reducing the ability of responsible companies to continue to operate and innovate.

We urge others in the genomics community to make their voices heard on these issues. Let the FDA – and, if you’re based in the USA, your political representatives – know that regulation of genetic testing should be based on evidence, not fear, and that any attempt to unreasonably restrict your access to your own genetic information is unacceptable.

Inbreeding around the world, gene-environment interactions and sales of genetic tests

The picture above shows the relatedness of parents across different populations throughout the world; for reference, 0.065 is the average value for a first cousin mating. It comes from a paper out in pre-publication this week at the European Journal of Human Genetics, which estimates the level of inbreeding (or “consanguinity”) of parents by looking for sections of the genome where individuals inherit an identical piece of DNA from each parent. Such “runs of homozygosity” are a sure sign of inbreeding, as both parents will have inherited the bit of DNA from a recent common ancestor: the number and length of these sections can be used to find out how many generations ago the common ancestor lived, i.e. how closely related the parents were (cousins share a grandparent, second cousins a great-grandparent, and so on). In the plot above, we can see a high degree of cousin-marriage in Middle-Eastern cultures, and somewhat more sadly, high degrees of inbreeding in the Native American populations, due to the collapse in their population sizes. [LJ]

For those interested in gene-by-environment interactions the latest issue of Trends in Genetics includes a review article by Carole Ober and Donata Vercelli on the challenges of this area, illustrated by examples from asthma research. In particular they highlight the difficulties of moving G-by-E studies from examination of known candidate genes to genome-wide association. More interactions, this time of the protein-by-protein kind, are the subject of an article by Soler-Lopez et al. in this month’s Genome Research. They looked for interactions relating to Alzheimer disease using a combination of computational and experimental strategies, identifying 66 genes that putatively interact with known AD-related genes. The authors focus on the potential roles of neuronal death regulation and pathways linking redox signalling to immune response in AD pathology. [KIM]
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A decade of genomics, 60 new genomes, parenthood and sharing genetic data, and more on data return

To celebrate 10 years since the back-to-back publications of complete human genomes in Science and Nature, Science has published series of articles looking back at the last 10 years of genomics, and forward to the future. The article contains short essays from Francis Collins and Craig Venter, the former talking about some of the successes of medical sequencing (including giving a name and photograph to the exome-sequenced IBD patient I discussed a few weeks ago), and the latter discussing how far we still have to go before genomics can reach its potential. Baylor’s Richard Gibbs talks about how the large-scale technical discipline of genomics and the biological subject of genetics are starting to re-merge, after the Human Genome Project saw the two diverging, and there is an oddly inspiring comment from theologian Ronald Cole-Turning about how genomics is redefining our vision of humanity.

Of particular interest is an article by Eliot Marshall on why genomics hasn’t yet had a large effect on medical practice, and what needs to be done to allow the genomic revolution to trickle into medical care. He argues that scientists and doctors need to meet each other half way; scientists need to focus more on showing the direct clinical utility of genomics, whereas doctors need to be more ready to accept new technologies and discoveries, and adapt the way they practice medicine to make full use of them. [LJ]

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HiSeq doubles its output, a next-gen sequencing primer, and return of genetic data to patients

Illumina CEO Jay Flatley announced that an upgrade to their HiSeq 2000 platform expected this spring will allow users to generate 600 gigabases of sequence (the equivalent of 5 high quality human genomes) per one-week run of the machine. This would essentially double the current throughput of the platform and propel Illumina even further ahead in the arms race of delivering vast quantities of low cost sequence data. [JCB]

Over at Golden Helix, Gabe Rudy has just completed a three-part series introducing readers to the promise and challenges of new DNA sequencing technologies, which is well worth a read for those just starting out in the analysis of next-gen sequence data or who have a more-than-casual interest in the current state of the field. [DM]

This month’s edition of Trends in Genetics includes a review article on the ethical issues raised by the feedback of individual genetic data to research participants by Bredenoord and colleagues. This has long been a subject of debate, but the recent increase in studies that assay a large number of genetic variants (such as genome-wide association studies and whole-genome sequencing studies) has brought this issue to the fore. There is currently no consensus on how to deal with this, and in my experience the approach favoured has varied both between projects and between the ethics committees that have assessed them.

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Reader survey results: digging a little deeper

Thanks again to the more than 250 of you who completed our reader survey a couple of weeks ago. We reported the basic demographics of readers in a post last week, and promised you some more detailed analysis this week – particularly of the two questions where we gave people the option of adding their own thoughts as free text.

There’s no way we can present every nugget of interesting information emerging from the survey, but we thought it was worth digging into a few of the more obvious or unexpected features of the data. Firstly, a little additional analysis of the more quantitative data emerging from the survey.
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Digging deeper into my disease risk

When Daniel first asked me if I wanted to be involved in Genomes Unzipped, I was one of the more hesitant participants.  I weighed up the pros and cons, but in the end what sold me was that after almost a decade of curiosity I finally had the opportunity to find out my genotype for the hereditary haemochromatosis (HH) variants in the gene HFE.  But things didn’t unfold quite how I’d expected, and I’m still left with some unanswered questions about HH in my family.

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Friday Links

Over at Your Genetic Genealogist, CeCe Moore talks about investigating evidence of low-level Ashkenazi Jewish descent in her 23andMe data. What I like about this story is how much digging CeCe did; after one tool threw up a “14% Ashkenazi” result, she looked for similar evidence in 23andMe’s tool. She then did the same analysis on her mother’s DNA, finding no apparant Ashkenazi heritage, and to top it all off got her paternal uncle genotyped, which showed even greater Ashkenazi similarity. [LJ]

A paper out in PLoS Medicine looks at the interaction between genetics and physical activity in obesity. The take-home message is pretty well summarized in the figure to the left; genetic predispositions are less important in determining BMI for those who do frequency physical excercise than for those who remain inactive. This illustrates the importance of including non-genetic risk factors in disease prediction; not only because they are very important in their own right (the paper demonstrates that physical activity is about as predictive of BMI as known genetic factors), but also because information on environmental influences allows better calibration of genetic risk. [LJ]

Trends in Genetics have published an opinion piece in their most recent issue outlining the types of genetic variants we might expect to see for common human diseases (defined by allele frequency and risk), and how exome and whole-genome sequencing could be used to find them.  They give a brief, relatively jargon-free, overview of gene-mapping techniques that have been previously used, and discuss how sequencing can take this research further, particularly for the previously less tractable category of low-frequency variants that confer a moderate level of disease risk. [KIM]

More Sanger shout outs this week; Sanger Institute postdoc Liz Murchison, along with the rest of the Cancer Genome Project, have announced the sequencing of the Tasmanian Devil genome. The CGP is interested in the Tasmanian Devil due to a rare, odd and nasty facial cancer, which is passed from Devil to Devil by biting. In fact, all the tumours are descended from the tumour of one individual; 20 years or so on, and 80% of the Devil population has been wiped out by the disease. As well as a healthy genome, the team also sequenced two tumour genomes, in the hope of learning more about what mutations made the cells go tumours, and what makes the cancer so unique.

I have to say, this isn’t going to be an easy job; assembling a high-quality reference genome of an under-studied organism is a lot of work, especially using Illumina’s short read technology, and identifying and making sense of tumour mutations is equally difficult. Add to this the fact that the tumour genome is from a different individual to the healthy individual, this all adds up to a project of unprecedented scope. On the other hand, the key to saving a species from extinction could rest on this sticky bioinformatics problem, and if anyone is in the position to deal with it, it’s the Cancer Genome Project. [LJ]

Tasmanian Devil image from Wikimedia Commons.

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