Your body is a complex system with so many components and moving parts, that perhaps it is a wonder that serious problems do not occur more often. It is often a self-correcting system with amazing checks and balances built in to ensure viable performance for most of your life, or at least long enough to ensure that your offspring can reach the stage of further propagation. (Yes, this is the very unromantic, utilitarian version of a post.)

For you see, while we are amazing functioning biological systems with an uncanny built-in lack of our own appreciation and gratitude for all that biological wonder, the truth is, in all of that complexity you will always, always, always find problems. The trick after looking into a genome is to figure out what information is critical - there are guidelines constantly being developed for this - as well as how to determine the validity of some of the obscure information that can be found. Rare variants, and mutations unique to an individual, can have sparse scientific background information available. They could even be incorrectly associated to a disease or condition.

The reality is that we all harbour some deficiencies to complement our perfections.

This theme is perhaps not as readily appreciated because these deficiencies can come in all shapes and sizes, ranging from mild impact, to serious diseases, depending upon what got randomly broken in that biological program of yours called genome. Yes, it is a program after all. A program so intricately designed, that in theory we could take this information, clone and recreate a human being.

Even though I study such deficiencies and perfections from the perspective of human genetics, I am still amazed at how wonderful and complex our system is. Who is to say to what degree these so called deficiencies might have played some yet unfathomable role in progression of the species?

But this was to be a sober, unsentimental version of a post, so let’s get back to it.

Not too long ago I had an opportunity to perform an interesting investigative report on the merits of genome sequencing of a family afflicted with inherited thrombophilia. It was brought forth by a doctor who had a great grasp of genomics. I was genuinely impressed with this doctor, so I included complex details in my reports about the applicability of genome sequencing technologies related to such a condition. Speaking of biological deficiencies, thrombophilia is a condition that leads to increased tendency of forming clots in your blood. I wanted to discuss this episode as it demonstrates so much about the fascinating complexity of genetics. Anyone who ponders genome sequencing should ponder about these following topics as well, be it a patient or a healthy individual.

Life can be seemingly normal, as everything is working fine, until a clot is formed and leads to plugged blood vessel. I probably do not have to tell you that plugging any pipe is usually not a desired event in any typical context, so when it happens in your body, it can be outright dangerous! Thrombophilia is a serious condition that might not even be suspected until a family history is revealed, or a serious condition develops.

This particular condition is of the complex type, having many potential mutations contributing to it, with at least around 20 well established genes. When I contacted the diagnostics laboratory at Yale School of Medicine, one of the leading laboratories investigating the genetics of patients with thrombophilia, their number of genes selected for thrombophilia studies is about 40 now.

Furthermore, both environmental factors and ethnic backgrounds exhibit their own influences in affecting the risk of plugging your veins with a clot (the official term for that would be venous thromboembolism, so get ready for it here).

For example, known precipitating conditions for plugged blood vessels can include cancer, surgery, trauma, long term immobilisation, pregnancy, and even long haul flights. Seriously, this is why you are supposed to move around every so often if you are stuck in a same position for long periods of time! Your blood could be pooling somewhere in the nooks and crannies of your vessels and be prone to clotting. This is a good recommendation even if you do not have predisposing genetic factors!

Once a clot is on the loose, it is like trying to flush all the pages of the worst book you ever had to read down the toilet. They might flush without incident, or it can lead to very inconvenient situation. So remember, to avoid the blocking of your veins, move around, even for just a bit, if your work requires you to be stuck behind your desk for long hours at a time. This is probably more of a reminder for myself then preaching to anyone else in particular. But sharing is caring. ;)

Then there is the impact of ethnicity. This is still often overlooked how a specific heritage background can influence your genetics and therefore how you interact with the world. While genomic studies are rapidly becoming standard all around the world, the majority of studies have been done on Caucasians, and the gaps of knowledge are still rapidly attempting to be filled. Thrombophilia is a perfect example of how different backgrounds can influence the exhibition of a particular condition.

To wit, here is a quote I used in the doctor report as well: “Several lines of evidence suggest that the [venous thromboembolism] incidence is the highest in individuals of African ancestry, followed by Caucasians, intermediate in Hispanics, and the lowest in Asians. The ethnic variations might, [only] in part, be ascribed to disparities in lifestyle habits, the distribution of obesity, the prevalence of cancer and infections, the proper use of prophylaxis, the rate of diagnosis, and the accessibility to medical care [and] diverse genetic backgrounds among ethnicities should be taken into account.”

People of Asian ethnicity are not completely off the hook though, and we will get back to this mystery shortly. First, here is another opportunity to discuss the biological complexity. You see, the reason why inherited thrombophilia can include so many potential genetic causes to create a problem is because like many biological processes, they are part of complex pathways with many components. Many enzymes are involved in ensuring when blood should clot or not. So the process can be disrupted in many different ways. Sometimes it is by having components not working properly. Sometimes it is the opposite and can have components working too much. Imagine if one of the robots in a factory assembly line started working too fast or not enough. Someone would probably be at least mildly unhappy about that. Enzymes in your biological pathways are like those robots in the factory assembly line. Put one out of tune too much one way or the other, and the biological process is in trouble.

Thrombophilia is a blood disease where mutations (or more appropriately, variants) were found in the DNA that results in some enzymes working too much, some not enough, or some can be completely lost. That’s like someone in your factory business deciding to stealthily remove or destroy one of those factory robots. That creates an even bigger problem! Can the rest of the system in the assembly line cope with such an alteration? You get the point. Often times, nature has a backup system to be able to handle such a challenge. But not always, and losing a component is usually not good. Oh, you know, like your eye or your kidney for example. You can do just fine with one, but it just is so much better with both.

Variants that lead to loss of normal function are the most common, and in thrombophilia, literally hundreds of such variants with biological consequences have already been identified in humans. For example, variants discovered in just few blood clotting genes - SERPIN1, PROC, PROS1 - number in at least 200 for each gene! They all can have varying degree of impact, so you can see what a great gamut of possibilities there could be. In fact, these are some of the most common affected genes that are screened when studying thrombophilia.

And here we come back to further information on ethnicity. While Asians appear to have the lowest incidence of venous thromboembolism (a plug in your circulating blood), that same reference already quoted above had this to say: “Lines of evidence have suggested that the prevalence of [SERPIN1, PROC, PROS1] deficiencies in Asians are much higher than those in Caucasians, in both general population and [venous thromboembolism] patient settings. […] Therefore, natural anticoagulants dysfunction are the major risk factors for [venous thromboembolism] in Asians.”

So how do you explain the paradox that Asians present some of the most frequent mutations for clotting potential and yet exhibit some of the lowest incidences of plugged veins? I will tell you: I don’t know and it appears that nobody knows yet. But one suggestion shows you another layer of complexity involved: that variants could be present that provide protective role. Like a biological Robin Hood, doing a molecular good for collective benefit of your entire body. Such mutations are much more difficult to discover because healthy people don’t study themselves as vigorously as sick people, for obvious reasons. But it doesn’t change the fact that variants providing benefits are also present, and such knowledge would be worthy of having.

But not to fret, luckily for all of us, human genomes are being sequenced at a more and more rapid pace, with the whole world jumping onto the band wagon, and Asia is keeping up with the international race. An example is a current project entitled GenomeAsia 100K. That number at the end implies how many individuals will be included across Asia in the completion of this project.

I attended the annual conference of the America Society of Human Genetics in mid-October of 2016, which was hosted by Macrogen, a genomics company based in Soul, Korea, that is spearheading this project. At the time, 234 ethnic groups across entire Asian continent were being assessed. It makes sense to study a population of a continent that comprises more than 60% of all the people in the world (and just four countries are accounting for 50% of the world population!) The vast majority of these genomes will be for medical purposes. The computational power to handle such enormous amount of data is processed by Singapore’s brand new National Supercomputing Center. I would love to see one of those!

Ok, for the final twist. As part of the final report that was delivered, a summary of current professionals’ recommendations on testing families with inherited thrombophilias was provided. And while the application of sequencing in thrombophilic cases is gaining ground and excitement, the latest guidelines suggest against testing of family members due to lack of immediate utility of influencing treatment. This is a common case with sequencing, as there might not be immediate treatment benefit. I happen to disagree in one regard though, and that is perhaps because the guidelines typically refer to blood work that does not include sequencing. In this case sequencing could still provide very valuable information on pharmacogenomics information. Some medication that is used in individuals afflicted with thromboembolism can include famed blood thinners such as Warfarin, which are known to have important pharmacogenomics information associated with its use. A person who has thrombophilia running in the family, and who might be sensitive to such medication, could potentially benefit from such information. So in this case the report included the reasons for and against sequencing. Application of genome sequencing is definitely often a controversial issue!

The bottom line is that every disease or condition can harbour similar complexities as described here, and should be viewed from a variety of angles prior to deciding for best course of genome sequencing. At Merogenomics Inc., we study such information and bounce it by different experts, including the medical community with relevant exposure to genomic technologies, in order to help provide access to quality service providers. If you are seeking information on inherited diseases and genome sequencing, we are here to help. There is so much information to be gained from genome sequencing, but it might not be for everyone. If you like the work produced by Merogenomics Inc., please let us know by supporting it. Show us you liked it, or forward it to those who would enjoy it. It is always a great topic of debate!

This article has been produced by Merogenomics Inc. and edited by Marcia Craig, Ph.D. 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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