Tuesday April 12 2016
Almost 600,000 people were screened for genetic conditions
"Some people appear to be born with 'superhero DNA' that cancels out genetic diseases like cystic fibrosis," BBC News reports.
A study of more than 500,000 people found 13 people who should have developed genetic conditions, but apparently didn't.
The study turned on its head the traditional use of genetics by looking for healthy people whose genomes contained mutations in single genes believed to cause childhood diseases – such as cystic fibrosis – in everyone with that mutation. Or, as one of the researchers put it, "Study the healthy, don't just study the sick."
The researchers chose childhood diseases, as most people in genetic surveys are adults, so the disease should have developed by then.
Ideally, the researchers wanted to find out what it was about these people that made them resistant to the disease mutations. However, they cannot re-contact the individuals because the study protocols stated that all survey data would remain anonymous.
This not only makes it hard to follow up on possible causes, it also means that researchers cannot check they are truly resistant to the disease, rather than there being any simpler cause, such as errors in the records.
While this study raises more questions than answers, it does illustrate the potential benefits that large, population-scale, genetic surveys may bring.
In the UK, a promising project is the UK Biobank – a charitable project that recruited 500,000 people aged 40-69 in 2006-10, to look at how genetics impacts on health outcomes.
Where did the story come from?
The study was carried out by researchers from the Icahn School of Medicine at Mount Sinai, New York; 23andMe; BGI-Shenzhen; The Children's Hospital of Philadelphia; Lund University; Ontario Institute for Cancer Research; Sage Bionetworks; iCarbonX; and Boolean Biotech Inc.
No funding information was available. Several of the authors work for commercial gene sequencing companies, which means they have a financial interest in the results. The study was published in the peer-reviewed journal Nature Biotechnology.
The UK media, on the whole, did a good job of accurately reporting the study. However, they did not all point out that the results could be caused by recording errors, as the researchers were unable to contact the participants.
The Mail Online's use of a photo of the mutant superhero Mystique, from the X-Men series of comics and films, was a little fanciful. While the 13 individuals identified in the study may have an impressive level of "genetic immunity", we doubt that extends to shape-shifting abilities.
What kind of research was this?
This was a retrospective analysis of genome data collected for a variety of purposes, including commercial "disease scan" services and academic studies. The researchers had access to varying levels of genetic detail from the different studies, and to records of people's self-reported medical conditions. They wanted to find individuals who had genetic variants that would usually have caused one of a number of serious diseases that start in childhood, but who did not report having that disease.
What did the research involve?
Researchers screened 589,306 genomes from 12 different databases, looking for mutations in 874 genes believed to cause 584 diseases. They compared the disease mutations to records showing whether people said they'd had the diseases.
They filtered out gene mutations where the candidate gene was only weakly linked to the disease, or where the disease is not thought to affect everyone who carries the gene, or where the disease was mild enough that it could have gone unnoticed. The aim was to find people with a genetic mutation that the researchers were confident should have caused a serious illness before adulthood, but which the people involved had not reported having.
The researchers worked with different levels of detail, from whole genome genotyped cohorts to whole genome sequencing cohorts. Genotyping means searching a genome for known genetic variants, while sequencing means determining the exact sequence of a length of DNA. Sequencing a whole genotype is more difficult and expensive. They were unable to contact the people identified as being potentially resistant to their genetic mutation, because consent forms for the original genome sequencing did not allow later researchers to identify and contact the individuals.
What were the basic results?
The researchers say they found 13 people with mutations to one of eight inherited (usually rare) childhood diseases, which would be expected to cause serious disease before the person was 18. These were:
- cystic fibrosis – which causes problems including excessive mucus in the lungs
- Smith-Lemli-Opitz Syndrome – a metabolic disorder that prevents normal growth and intellectual development
- familial dysautonomia – which prevents the nervous system from working properly
- epidermolysis bullosa simplex – which causes skin blistering
- Pfeiffer Syndrome – which causes skull deformity
- autoimmune polyendocrinopathy syndrome – which causes a steep drop in the body’s production of hormones
- acampomelic campomelic dysplasia – which affects bone growth
- atelosteogenesis – which also affects bone growth
How did the researchers interpret the results?
The researchers say the study opens the possibility that "genetic modifiers may be more common than believed," because they found people with genes thought to be "completely penetrant" – i.e. to always cause disease – who nonetheless did not show signs of disease.
They say that individuals who show possible resilience to penetrant genes are still "extremely rare," so future studies will need to look at very large groups of genomes to find any. They add that future studies should allow researchers to contact people after the study has ended, so that findings can be investigated and followed up.
They say that their inability to contact individuals means they "cannot exclude straightforward explanations," including "somatic mosaicism," which is when genes are expressed in some cells of the body, but not others.
The researchers have presented some intriguing results, but their inability to contact the individuals identified in the study puts the results in question. As well as the explanation the researchers put forward, it's possible that the results are simply due to mistakes in the records.
The researchers hoped to be able to identify conditions (genetic or environmental) which might protect an individual from a disease such as cystic fibrosis, which they are genetically programmed to develop. However, the current study does not even confirm that such individuals exist, never mind help us to understand possible causes. Sadly, the practical application of the research is likely to be many years away.
This type of research is also very expensive. The researchers said they would ideally use whole genome sequencing, as opposed to the cheaper targeted sequencing used by most commercial firms, but that this would cost up to $1,500 per sample, which would reduce the numbers that could be screened.
Though the researchers and media have lamented the inability to confirm the findings by contacting the individuals, this is a tricky area that should not be taken lightly. Genetic counselling is recommended both before and after any genetic tests, for the person to decide what level of detail they want to find out. In this case, the news was likely to be good, but in many cases the news may be devastating or lead to unnecessary anxiety about the future for themselves or their offspring. There may also be health and life insurance implications.
While the research suggests a new way of looking at genetics and disease, it's hard to see a treatment for any disease based on this emerging in the short term.
The researchers have announced that they have launched a US-based project, called The Resilience Project, which aims to build upon the work of this study by hopefully identifying named volunteers with a proven genetic resilience. It will be interesting to see what insights the project may uncover.