Progress in the world of medical genetics 2020
Big conference, big news, big medical impacts
One of the largest conferences dedicated to human genetics is put on by the American Society of Human Genetics every October. This year, due to the COVID-19 pandemic, not surprisingly the conference was online, allowing for an easy opportunity to attend. Merogenomics was involved in the same conference four years ago in Vancouver which resulted in the birth of this blog with its very first post dedicated to the ASHG conference overview. Merogenomics was excited to return to this great scientific event on human genetics.
There were many great themes emerging from the talks. The biggest take home message is that medical genetics continues to grow at an enormously rapid pace, with consistently more patients all over the world having their DNA sequence decoded to help with their medical management and to help discover novel causes of the conditions affecting them - from rare diseases to more common health issues such as breast cancer or hyperlipidemia. Even really complex traits like infertility are being probed for influencing genetic factors. No condition escapes the microscope and some completely new diseases are described as well. It is becoming clear that medicine will be dramatically reshaped in the near future. Read on to find out why not right now (when it already should be).
An emerging theme is that our understanding of the complexity of genetic influences on our traits in health and disease is also constantly on the rise. As more patients and volunteers are sequenced and this information is correlated to different traits, far more nuances are being fished out. A really interesting aspect that continues to build supporting evidence is the involvement of structural DNA variants in disease, especially those that involve large segments of DNA being affected - whether deleted, duplicated, inverted, moved to a different location or a combination of all of these. As the number of people who have their entire genomes decoded increases, and as the technology improves in assessing these genetic events, it becomes clear that structural variants are a common feature in human disease.
Predicting future health risks
Not only are we seeing more causative mutations for a myriad of conditions, but also more and more of the DNA mutations that have tiny effects (that can collectively influence complicated trait outcomes) and they are being pooled together for some sophisticated predictive tests. These are called polygenic risk scores, and normally they are notoriously difficult to develop because of the number of people who need to be tested, but more and more of these are being produced. Eventually we will be able to get so much predictive information from our DNA sequences that medicine will truly enter a stage of being preventative to a significant measure. We will be able to look at genetics (combined with other biomarkers, so your other biological data that can be tracked in your body - even something as simple as your temperature) and start predicting numerous medical outcomes, and then take appropriate preventative measures. This is, of course, already the prime purpose of screening yourself with full genome sequencing, to find out if there are any potential risks to your health based on mutations in your own DNA and to take appropriate preventative actions but down the road your genome sequence would continue to serve you because if you decode yourself now you can recheck your genome sequence in the future at any time as more genetic knowledge continues to accumulate. If you have had your genome already decoded, we always recommend to reinterpret your data every few years with the latest information that is personally pertinent. But polygenic risk scores could substantially help increase the understanding of expected risks related to different diseases.
A good example of a polygenic risk scores that is already available to doctors is for different cancers, but some really interesting ones are being developed, for example risk scores for the development of stuttering!
The predictability of outcomes is also likely to be enhanced through efforts in understanding the driving factors that affect disease penetrance. Why do some people with an identical mutation experience no symptoms while others experience a disease? Such a great variability in the potential outcomes of genetic mutations is one of the underlying reasons that restricts doctors from knowing exactly how to best utilize medical DNA testing in their practice, especially since for many clinical mutations these probabilities of disease development have not yet been effectively worked out. One possibility is that these outcomes are affected by the amount of the protein produced by the mutated gene. A gene within the DNA is just a stored information. It then needs to be copied into a blueprint that is used to produce the final product of importance: a protein. Proteins are like the molecular robots doing most of the work inside a factory (called the cell) that ensure that the cell is actually “alive”. Other proteins are the scaffolding of the structures that ensure the cell factory looks the way it does. So, you go from a gene, to a copied blueprint (the actual name for that is transcript, which is in a form of an RNA which of course is chemically very closely to resembling what the DNA is made of), into a molecular robot protein. What could be affecting the production of these proteins? Things could include: other genetic mutations that might be impacting how much the gene is expressed (how much transcript is produced); how the transcript RNA is produced; and finally how it is utilized.
Combining molecular omics data
Related to that is another trend of combining of different biological data along with the DNA sequence which increases the understanding and predictability of trait outcomes. This includes the transcriptome (or a measure of all the gene transcripts) which has also already entered clinical use, especially in cancer molecular analysis. Which genes are actually used in cells at any given time it is referred to as gene expression, and the power of detection is so precise that this is being measured and analyzed on a single cell’s level, meaning in a given group of cells being assessed for their molecular behaviour, gene expression is studied in every single cell! This allows us to understand how complex the biological behaviour of cells is within any given tissue as they interact with their environment. RNA analysis is already used in cancer in both predictive tests prior to onset of cancer or in the analysis of cancer biopsies to determine a potential treatment course, and also in the prognosis of cancer, clarification of a diagnosis and the understanding of its origins.
But the focus that continues to grab massive attention is epigenetic studies. These are chemical “decorations” on the DNA which might influence how the DNA is used as a catalogue of information. If you add a specific chemical on top of some DNA in a specific spot, it might mean that specific genes will no longer be used, or vice versa. What drives these modifications of DNA? Environmental influences, which is why this is such a big area of interest. Think of it this way - if you drink coffee every morning, you will drive specific epigenetic alterations in certain cells of your body that would not be observed in a person who does not drink coffee. One that stood out was epigenetic changes in children born with assisted reproductive technologies. Very specific area of research. Down the road, we still need to figure our the long-term consequences of such changes, and how permanent they are.
Epigenetics can also refer to environmentally induced chemical modifications of certain proteins that they themselves regulate how the DNA is used. It is big and interesting because it is fundamental to the nature vs. nurture.
Another big molecular arena of investigation is how RNAs are actually spliced together which also potentially influences the final outcome of how a gene is used. Think of it that a single gene can produce multiple different RNAs, depending on how the components of that gene are used to create the RNAs. When the gene is copied into RNA, some of the fragments of the RNA have to be removed because they are not meant to be in the final product. When that removal process is completed (it is called RNA splicing), the final molecule is called mature RNA or mRNA, and it is mRNA that is the actual blueprint to produce a protein. But what you remove from RNA to produce mRNA can be variable, so that a single gene can be used to produce many different mRNAs. Some of this is on purpose, some of it will be by accident, and this also drives final health outcomes. Thus, how RNA is spliced into mRNA is also big area of investigation.
The final component of omics we shall mention is the study of proteins themselves which have their own journey of modification.
Every single step along that path from DNA to health trait development could be negatively impacted. Our current technologies allow us to investigate all of the complexities of these events: how DNA is mutated (genome information); how DNA is modified epigenetically (epigenome information); how DNA is used to produce RNA (both in terms of which genes are used and how the RNAs are spliced together - transcriptome information); and how the resulting proteins are built based on what the RNA blueprints look like (proteome information). These can all be pooled together for a very complicated picture of how your molecular biology drives your health outcomes. This is referred to as integrative omics, or the multi-omics approach.
These accomplishments are partially driven by sophisticated machine learning programs developed to sift through literally millions of medical records to start connecting specific traits of interest with millions of such molecular data points. It is a dizzying operation. And we are just getting started. The complexity of biology is that gigantically enormous .
Where the doctors at? Still timid of DNA testing
However, a theme that is shocking because it has persisted for so many years now, is that rank and file doctors are still far removed from taking full advantage of these technologies, especially the main one that is already so entrenched in medicine - the tool of DNA sequencing. While clearly more and more doctors are hearing about genomics and DNA testing, and more doctors are starting to use these sophisticated tests in their practice, the gap in use remains enormous and testing is dramatically underutilized despite years of advances and attempts to increase the awareness among practitioners. Merogenomics primary goal is to help close this gap by setting up clinics with access to medical DNA testing and we are keenly aware of the degree of apprehension and unfamiliarity that can exist among doctors and clinic workers when it comes to understanding the beneficial use of clinical DNA testing. If you are a doctor considering or using medical DNA testing in your practice, you are definitely a trend setter!
What are the biggest areas of utility? Cancer DNA testing always seems to be the top one, both in terms of affected patients as well as the investigation of risk for still unaffected family members. Pharmacogenetics testing is another arm of testing that is seeing increased interest and adoption, likely spurred by the fact that it can so easily provide actionable results. But the area that was especially of interest to us, and definitely consistently growing, is the use of genetic testing in affected newborns and even fetuses prior to birth. This area is expanding into the assessment of different conditions and birth defects. One big area of interest is definitely autism spectrum DNA testing, where novel genetic factors are continuously being uncovered. To top it off there is the field of cardiology which also sees a constant uptake of DNA testing. Merogenomics supports these areas with access to DNA testing in all of these fields (check out the links above), as we have been covering these trends with interest for quite some time, thus Merogenomics was particularly keen to attend these presentations to be kept up-to-date with the latest information. It should be mentioned, that Merogenomics always strives to make readily available the education, assistance and guidance that clinics and their doctors need to have the confidence to facilitate medical DNA testing in their practices with the right tools, right now!
What was one interesting (but not surprising) addition at this conference was a section dedicated to the genetics of COVID-19. The studies were enormous, including tens of thousands of individuals who have been infected. The ability for the research community to come together to initiate such large-scale studies is just mind boggling. They included data from biobanks (large-scale repositories of molecular information linked to health outcomes of individuals), clinical studies going on around the world, and even direct-to-consumer commercial tests. What these studies are fishing out using genome-wide association studies are potential genetic mutations that predispose people to infection by SARS-CoV-2, and even mutations that could increase the risk of hospitalization or result in severe outcomes (such as requiring a ventilator and/or being in a group at high risk of succumbing to COVID-19). A number of such genetic mutations were uncovered, and it will be interesting to see how they stand the test of time. Not surprisingly, most of these were related to immune function. But you can see that if COVID-19 becomes an enduring feature of our society, there may eventually be predisposition tests available, and the very first ones to hit the market are likely to be totally unvalidated, simply based on such initial reports. This is an endemic problem with DNA tests, especially the direct-to-consumer ones, and proper DNA test selection is crucial if one desires real versus goofy results.
But the genetic analysis did not just extend to patients. Data was also presented on the sequenced genomes of SARS-CoV-2 isolated from positive patients, and in the US, hundreds of such patient samples were decoded, which allows the tracking of not only the evolution of the virus as it mutates, but also the monitoring of how the virus spreads and enters a community, and how different strains are stopped from spreading. It is really fascinating and elaborate work (and a blow to those who want to peddle the notion that bulk of the SARS-CoV-2 tests are false positives, since the actual entire genome of the virus is being consistently showcased in random patients. Sorry to burst that beloved rumour to so many COVID-19 conspiracy theorists).
Human diversity, much bigger than our data
The final “big trend” was a common consensus about the lack of population diversity on which ethnicities have been studied thus far with DNA sequencing. The vast majority of all people sequenced up to now are Caucasians, representing more than 80% of the accumulated data, and it is well recognized that this trend, which does not seem to be subsiding at all, is to the detriment of all ethnicities, including the Caucasians. The genetic variation underpinning human health is very diverse between different ethnic populations, and if you are not Caucasian, but are taking a medical DNA test, you will be screened for genetic events that very well might not be representative of your ethnicity at all. Vice versa , we know that many human conditions are caused by rare mutations, and the greater the diversity of a sequenced population, the more likely we are to uncover important causative mutations, some of which could randomly appear in anyone, including the Caucasians. But the understanding of medical impact of such mutations might become more readily apparent when uncovered in other ethnicities, if such mutations were to be more prevalent than in the Caucasians. Once these mutations are uncovered and recorded, from any ethnicity, such information can help countless lives moving forward into the future, for anyone in the world. This is a well recognized problem and constant discussions and efforts are made to increase the diversity of sequenced population. Luckily, these numbers are constantly on the rise, globally, but proportionally the Caucasians continue to be disproportionately represented compared to the actual global ethnic population distribution.
American Society of Human Genetics Conference 2020, final thoughts after four years of blogging
Not everything was dedicated to medicine but it is evident that the primary utility right now of the human genome is to drive the progress of medicine, and the strides being made forward are enormous. The size of the conference itself also reflects this growing trend and it is not a trivial thing to even know how to select lectures of interest. But one thing is clear, medical progress through DNA testing is unstoppable and it is fascinating to watch its constantly expanding influence. Whether doctors are ready or not, DNA testing will soon be a foundation of patient care.
And to end, happy birthday Marie Curie!
This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.
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