The world of genome sequencing is fascinating in part because it is a continuously growing and evolving field. Every opportunity to attend a conference dedicated to this topic will provide you with new discoveries and further education. So imagine attending a conference dedicated around the sequencing of your own genome! A conference where every participant has had their genome sequenced, has had their results delivered, and as a part of the conference, for the first time will view their genome on an online app. And you get educated by the biggest names in the industry.

Sound far-fetched? It kind-of is, as there are probably not too many fields that can boast such a personalized approach towards conference attendees. But in the field of personalized medicine, where detailed diagnostic genetic information is collected, demanding that the medical care response be tailored specifically to an individual, perhaps the trend of personalized conferences could be a reflection of the industry trend. This personalized conference, aptly named “Understand Your Genome”, is a single-day meeting organized for all of the participants who have sequenced their entire genomes to obtain information of medical significance. For the background on the genome data component that a participant obtains prior to the conference, please refer to a previous post.

The “Understand Your Genome” conference is an event that is organized by Illumina, the world's leading producer of DNA sequencing machines. It takes place all over the world, and each city can apply to participate in these events. The majority of these have taken place in the US, while in Canada only Vancouver has hosted an event thus far. The sole exception is Boston, which has become a yearly host, and this year, it hosted this event for a third year in a row.

The conference took place in the elegant-looking Broad Institute, one of the local powerhouses of human genome sequencing. The list of speakers participating was large and many interesting tidbits of information were provided. It was a mixture of background education on genome sequencing and the latest advances in genomic medicine, delivered in a typical scientific presentation fashion, but certainly entertaining to follow.

Dr. Peter Goodhand opened up the day and spoke of the rapid pace of DNA sequencing taking place, with the current number of people with sequenced genomes estimated to be around one million people. Bear this in mind with regards to some other data I will present. By the year 2025, it is estimated that more than 60 million people will be sequenced, with more than 80% funded by healthcare to help improve health outcomes. Humans will be the most studied organism on the planet (if they aren't already!).

Drs. Stacey Gabriel and Heidi Rehm followed up with some of the technical aspects of personal genome sequencing for the “Understand Your Genome” program. The sequencing was performed at the Broad Institute, and what a powerhouse of sequencing it is! The numbers are just staggering: every 10 minutes, a new human genome is sequenced with 100 000 per year completed in that institute alone! How are we only at around one million genomes sequenced worldwide?

Together, that amounts to generating about 17 terabyte of DNA sequencing data per day. For comparison, it was noted that YouTube receives 24 Tb of new video data per day. So, in total, the Broad Institute manages 45 petabytes of data compared to 86 Pb managed by YouTube. That includes all of the videos ever uploaded on YouTube! And once again, we are talking about just one institute! No wonder there are projections that genomic data will overcome all other forms of data production in the world!

To obtain our genomes, 90 billion base pairs were sequenced. The sensitivity of genome sequencing instruments to detect singular nucleotide changes (also referred to as polymorphism, to produce the well-known acronym SNP), is over 99%. For small deletions or insertions of few nucleotides at a time (cheekily referred to as indels), sensitivity is 98.9%, and the overall sensitivity for all types of mutations, including more complex rearrangements, is 84%.

On average, about 5 million variants will be found in each individual. Depending upon the number of genes being analyzed (for “Understand Your Genome”, it was nearly 1700 genes associated with medical conditions), such variants are filtered against multiple databases that have accumulated past discoveries of variants involved or suspected to be contributing to disease. In some of the research that the institute participates in (BabySeq or MedSeq), they are already analyzing up to 5000 genes, so that is the direction that these tests are heading in the near future.

Such filtering dwindles down the variants to about 200-300. These are then analyzed with additional tools, where the majority (~70%) are discarded for technical reasons. Just over 10% are removed for genetic reasons (where variants were previously suggested to be involved in disease, but the manual review might suggest otherwise, as many variants do not have enough supporting evidence). Another 5% are removed due to their common frequency in the population. That leaves about 20-30 variants that are finally reviewed by a medical geneticist specialist who individually inspects the role of these variants in disease development to ensure that the reported information is accurate.

So in the end, only about 1% of the filtered variants are actually reported back to a doctor as either involved in a monogenic disease or a carrier status. For a MedSeq project participant (the study of genomic medicine in a healthy population), that would range between 0-7 reported variants. For a BabySeq project participant (the study of genomic medicine in newborns), that results in 0-2 reported variants.

The interpretation of the genome is by far the trickiest part of the equation, and where the expertise can make a huge difference. As genome sequencing is an emerging field, the vast majority of observed variants are either vary rare, or completely unique to a given individual, never observed before or to be seen again. This makes the interpretation very challenging, and often DNA information can be interpreted differently by different labs. This is still a major issue in this field, and it will take some time before tools are powerful enough for automated interpretation to have this problem solved. It will probably always persist to a degree, as that is the challenge of the uniqueness of our genomes.

On the other hand, because so many of our individual variants are so rare, it is worthwhile to share that information with public databases so that the interpretation of genomes continues to become more precise. Genome Connect allows patients to share their reports for this purpose.

Dr. Mark Daly went into another complicated area of genomics, related to common complex traits, including diseases. These common complex traits are derived from a contribution of many different variants scattered across the genome, sometimes hundreds, or even thousands, contributing DNA variations, as compared to diseases that arrive from mutations in single genes, which is what is typically studied and reported to doctors. And as the name implies, they are commonly found in our population. Dr. Daly commented that whereas a random person will have 0.04% chance of sharing the same monogenetic disease risk, with common complex disease this chance jumps to ~10%, between siblings it is about 30%, and between twins it is 50%.

The reason why these common variants can accumulate in a population to such a degree is because individually they cannot affect our fitness. But their collective impact can have negative consequences. However, because so many of these variants are involved, genome sequencing can be diagnostic for these traits but the prediction of their manifestation is quite difficult and incomplete. Such predictability is expected to arrive once data on millions of people is available.

Dr. Richard Maas, on the other hand, spoke of dealing with rare monogenic diseases in the clinic, including the discovery of new links between genes and disease states. Pinpointing the causative mutation is usually aided by sequencing multiple family members. Often this involves a trio case of parents and the affected individual, but Dr. Maas also pointed out that the sequencing of distant relatives can be more helpful as closely-related individuals might share too many variants to be properly informative.

Establishing a functional role of a mutation in the disease development might not be a trivial process. The easiest way of establishing such a connection is by finding the same mutations in a number of individuals in different families with the same disease, but it can involve more complex detective work, such as the study of mutations in model organisms, and even mutations in specific cell lines. Definitively not a small task. As an example, of the 249 cases in October of 2017 as part of the Brigham Genomic Medicine clinical research program, about a quarter of the cases were solved.

Even monogenic diseases are sometimes not as simple as the “mono” would imply. About 10% of cases are digenic, and even rare trigenic cases as well, such as recent genetic examples in cardiomyopathy, so it stands to reason that simple multi genic conditions will eventually be discovered, but will not quite belong in the category of common complex diseases. And even then, some genes involved in monogenic diseases can also apply to common complex diseases. It's a complicated world within your genes!

Dr. Eli Van Allen discussed computation oncology and the use of multi omics alongside big data to find a personal diagnosis. Just a few years ago, this would be nothing but a dream to cancer patients, with one of the first such examples of precision oncology described in the New York Times in only 2012. Since then, the strides forward have been so vast, that Dr. Van Allen mentioned that ideally every cancer patient should be sequenced to match a targeted therapy.

However, the cancer genome is profoundly rearranged, with thousands of problems discovered in every mutation type category you can imagine. This means that the manual interpretation on entire genomes is simply not possible if we are looking at its mass adoption in medical care. For this reason, the Broad Institute developed a computational program called PHIAL for the clinical interpretation of cancer genome sequencing data, which is now used in the CLIA laboratory setting.

While PHIAL stands for Precision Heuristics for Interpreting Altered Landscape, the name actually finds its origin from the Lord of the Rings! The Phial was a gift given to Frodo by the Elven Queen, Galadriel. It was a flask of water from a magic fountain that captured the light of the Erendil, the Elves’ most revered star. The Phial would radiate light in dark places and illuminate the path when all other light is gone. Sometimes nerdiness is truly beautiful!

Dr. Erica Ramos, who is a genetic counselor and a clinical lead at Illumina, talked about how the “Understand Your Genome” program assists with future interpretations of the human genome. Over time, Illumina has contributed approximately 95,000 variants to a ClinVar database, one of the most authoritative databases in clinical genome interpretation, and 99% of these have been accumulated from the “Understand Your Genome” participants. More than half of all the variants that are used by Illumina for their classification (as either pathogenic, benign, or variants of unknown significance or VUS), have been seen only once.

Using another large public database, the exome aggregation consortium (see video below), that collects information on variants from research all around the world to assess their commonality, allowed Illumina reclassification of nearly 10,000 VUS. The good news is that only about 0.001% of these VUS have been classified as VUS suspicious (classification only used by Illumina), or likely pathogenic. The rest were downgraded to either benign or likely benign variants. Over time, VUS that seem suspicious have been reclassified as likely pathogenic 50% of the time, or pathogenic 8% of the time. So they are pretty good when they do get suspicious about a variant. 

Dr. Robert Green, who oversees the MedSeq and BabySeq projects, discussed the possible general application of genome sequencing in a population. And indeed, he sees that the most likely immediate future mass use of this technology is population genetic screening for disease predisposition, with a push towards adopting the use of this technology earlier in life. Other immediate benefits include expanded pharmacogenomics screening, expanded carrier status screening, and prenatal testing. All of these services are already available here and now to varying degrees.

Further in future we are likely to observe the mass adoption of genome editing.

The current limitation on mass scale adoption is the reimbursement for tests. The reimbursers require proof of clinical utility and cost effectiveness, which are not easy studies to execute. For example, with the famous ACMG list of genetic conditions suggested to be disclosed to patients, it is not proven that these genetic conditions are actionable (treatable), if screened on a population scale. While treatment or intervention has been established for each condition, how this applies to each random discovery of mutations in such disease genes in a population is not known.

The absence of clinical utility of DNA sequencing runs the risk of leading to a fraud commerce, the sale of DNA tests that are divorced from scientific reality. And when scientific backing is present, it will likely result in health disparity, as the technology would only be accessible to those who can afford it. So establishing clinical utility for a wider adoption of genome sequencing in medicine is key.

Dr. Green’s team has recently published the results of one such study, to show that the median medical cost between incorporating genome sequencing versus standard care was less than $100 difference. But the most noticeable differences were observed between the participants. Patients who had utilized genome sequencing towards their care were more likely to alter their behaviour towards a healthier lifestyle, and were less likely to be disappointed with the experience, showing higher levels of happiness, empowerment and relief. Likewise, the participating physicians who utilized genome sequencing in their patient care were more likely to propose new recommendations, including health behaviour or medication use. Much of this data is yet to be published.

One of the confounding factors of being able to obtain clear-cut utility results is the disease penetrance, or the degree of the disease symptoms being exhibited by a person. One way to think about it is that because of variable penetrance, people can have only fragments of a disease and not just a full-blown disease. So instead, Dr. Green suggested that perhaps disease penetrance should be thought of in terms of longevity, where very long periods of time can be required for a disease to fully materialize. And therefore studies should reflect that when trying to assess disease development based on genetic factors.

While so many illustrious speakers offered their wisdom at the conference, simply too many to write about here, one of the highlights was definitely Dr. George Church. Dr. Church is a larger-than-life personality in the world of genetics, usually involved in the most advanced and cutting-edge programs. Or the most provocative, like the recent announcement of the synthesis of a human genome, and the pursuit of real risk of miscarriage. Perhaps his influential career was best represented by his disclosure slide which showed logos of dozens and dozens companies with which he is involved. Quite a pedigree of achievements from someone who, according to the person introducing him, also flunked out of Duke University, and for a while lived in a forest. You can't help but like this character.

The viewers were bombarded with a litany of projects, and only the briefest are mentioned here. It includes work on removing retroviruses from a pig’s genome in order to ready their organs for transplants in humans. This is an obvious important medical need that has to be solved as the number of transplant recipients far exceeds that of donors.

That's one way to go about it. Another is to look at organ development from scratch. The goal is to be able to master the manipulation of transcription factors with epigenetic changes, in order to control the cell development to such a degree as to initiate specific organ formation at a reduced time span than what is observed during human development.

Another big area of interest appeared to be the reversal of aging, a field that is making remarkable progress. At least 45 gene therapies have been suggested for anti-aging, there are 2 clinical trials with molecules for anti-aging that are taking place, and gene editing procedures are in animal pre-clinical trials. Perhaps we can expect to live longer in the not too distant future?

And what better way to close off a genome sequencing topic than with a new emerging technology offered by ReadCoor company, that allows DNA sequencing in three dimensional space (yet another of Dr. Church’s pet projects). In essence, this allows one to determine in a natural cellular space environment where the sequenced molecules are present (either DNA or RNA), and can even be implemented for mapping the cellular distribution of proteins. Obviously the hope is that such precision technology, providing special and functional detail, will further help to elucidate the molecular contribution to disease and its response to treatment.

But for now we have to contend with mere genome sequencing to peek into our potential health destiny. 

Happy genome exploring in the New Year!

This article has been produced by Merogenomics Inc. and edited by Kerri Bryant. 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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