by Carol A. Westbrook
Less than 100,000 people in the entire world have had their genome sequenced. I am now one of them. As I wrote in 3QuarksDaily in December, I went into this with some trepidation–you never know what bad news lurks in your genome! I promised to give a report of my results, and here it is.
To get my genome sequenced, I enrolled in Illumina's “Understand Your Genome” Program. Illumina is one of the few companies licensed by the FDA to perform whole genome sequencing (WGS) for medical diagnosis–other consumer products such as Ancestry.com, National Geographic's Geno 2.0, and 23andMe, provide only a limited analysis. I sent in a blood sample in November, and in February received a detailed analysis by Illumina's genetic counselors. In March I attended the “Understand Your Genome,” conference, where I received an iPad with my WGS uploaded into the “MyGenome” app, training on the use of the app, and a fascinating daylong seminar which explored the interpretation and medical uses of genome sequences. My daughter, a medical student, attended the program with me.
Viewed on the iPad, my genome sequence consists of two similar but not identical, parallel lines of the letters, one from each chromosome. There are only 4 letters, A,C,G, and T, representing the four DNA nucleotides that are aligned to make the sequence. A human sequence is about 6 billion nucleotides long, with half inherited from one parent and half from the other, and a few new mutations that arose on their own, probably less than 100. Thus, from a family perspective, a person's DNA sequence is 50% identical to each of his parents, children or siblings, 25% identical to grandparents, grandchildren, and so on to my distant relatives. My genome is very similar to every other person's, but it is not identical to anyone's. No one has ever had the same DNA as me, and never will — it is what makes me uniquely me.
How different am I from everyone else? My genetic analysis showed that I have 3,524,186 individual nucleotide differences, from the “average” genome to which it was compared, reference genome hg19, NCBI build 37. This is about 0.05% variation, which is typical for most people. To put this in perspective, if you were to compare my DNA to that of our two most closely-related primate species, bonobos and chimpanzees, the differences would be over 4%; when comparing me to Neanderthal man, however, you would find only 0.3% variation. So 0.05% is small enough to make me human, but large enough to make me a unique individual.
Of the 3 million variants in my genome, only about 13,000 were found that produce change in the protein coding sequences of genes, impacting on 1,222 “conditions” (diseases or traits). The great majority of these changes were considered to be “benign,” meaning they been validated not to cause disease, or they were “variants of unknown significance, ” or VUS. A VUS have not been linked to disease, but it has not been excluded, either; many of these VUS's will become clear as more genomes are sequenced and the database expands. We are not sure what to make of the other 3,511,186 variants that occur outside of genes–some may be significant but most are probably silent passengers that were picked up during evolution. Again, we'll learn more as the database expands.
Of the1,222 conditions for which I have variants, only 4 are significant. Three are genes for recessive diseases, which makes me only a carrier, since you need two copies to have a recessive disease. Two these genes, galactosemia and Bardet-Biedl syndrome, are very rare debilitating diseases of children. My own children have a 50% risk of being carriers, though it is very unlikely that their partners are carriers too, so there is little risk that their future children will have the disease. They could be tested prior to having my grandchildren. The third recessive gene is hemochromatosis, a disease of iron overload, which is easily treated in its early, silent stages, but can cause liver cirrhosis if it is not. The hemochromatosis gene is quite common, as one in 200 people of European background are carriers. In fact, it is possible that some of my relatives may actually have the disease; fortunately for them, hemochromatosis is easily diagnosed with a blood test for ferritin, or an inexpensive DNA test.
My surprising result was that I have both recessive genes for TPMT deficiency which, strictly speaking, is not a disease but is a metabolic variation in drug metabolism. A deficiency in TPMT or “thiopurine S-methyltransferase” makes me unable to metabolize three medications: 6-mercaptopurine, 6-thioguanine, and azathioprine. If I take one of these medications I would get deathly ill; fortunately, these are drugs only used for leukemia treatment or transplant. I will keep this in mind should I ever need them. About 0.3% of the population also has TPMT deficiency.
Now on to the diseases which develop later in life, what I call the “AARP diseases.” Many participants opted out of learning whether they have one of these scary genes, but I had already decided that I wanted everything revealed. For cancer risk, I was pleased to find that I don't carry any of the known genes. I was also relieved to find that I don't carry any of the known genes for neurologic conditions, in particular the genes for Parkinson's disease, which affected my late mother when she was in her 80's. I also do not carry the genes for early-onset Alzheimer's dementia. Illumina does not analyze for late-onset Alzheimer's dementia, which is the more common form that attacks older adults, though we were given the coordinates if we wanted to check on our own. To do this I used the MyGenome app and punched in the WGS location. I found that I have one copy of APOE-4 — increased risk — and one copy of APOE-2– protective. My risk, then, is neutral. Whew! Looks like I lucked out in the AARP diseases.
That, in a nutshell, is my genome report. Was it valuable? Absolutely. The value to me was not in learning what I have, but what I don't have. I was reassured that I am reasonably healthy, and likely to be so for a few more years. I don't have an increased cancer risk, I don't have a tendency to blood clots. Except for TPMT deficiency I don't have any drug metabolic variants, which means my risk of unexpected side effects from medication is low. My health care costs are likely to remain lower than average and I will probably go on being healthy for a long time. These conclusions will influence both my health insurance choices and my financial planning for retirement.
You can begin to see the impact that WGS might have on your own health, as well as on your health care costs. Today there are only two medical uses for WGS that are accepted and reimbursed by insurance: the identification of unknown diseases of children, and cancer genome analysis for chemotherapy targets–and the cancer use is still not widely accepted. But there are many more ways we could improve medical care with WGS. Imagine the complications and deaths that would be avoided, and the wasted health dollars that would be saved, if your pharmacy had a list of your drug metabolism variants so they could identify–in advance–if you are likely to have serious side effects, or if a particular drug won't be effective for you. We could actually do this today! And if a person knew in advance he had a tendency to some diseases and not others, he could focus his health care dollars on screening and prevention strategies where they will have the most impact. This will be even more relevant as our knowledge base expands.
I cannot recommend WGS to everyone — yet–but it's in our future, especially as the price is expected to drop below the $1000 mark, less than the cost of a single CAT scan. At present, too few genomes have been sequenced and correlated with medical information to be able to interpret much of what is present in a WGS. This will change over the next few years. There are projects throughout the globe that are doing just this, such as the 100,000 Genomes Project in the UK and The Million Human Genomes Project in China. In the US, the Personal Genome Project is collecting sequences such as mine to do these studies. The potential impact of WGS technology is enormous, as it will lead to more effective, personalized treatment of disease and, more importantly, to better health.
At some time in the not-too-distant future, everyone will have his or her own WGS. I'm pleased to be an early adopter.