Just as we are getting to grips with the idea of sequencing millions of genomes, evidence is suggesting that even one per person might not be enough. The dogma that each of us has one genome to sequence is crumbling under the weight of evidence. It seems that we might be genomic mosaics and the new paradigm could be ‘one human, multiple genomes’.
The most common source of our multiple human genomes is cancer. Genetic disease is conventionally thought to arise from inherited genetic lesions found in the germ line— the sperm and eggs that combine to form the first human cells from which we all grow. In contrast, cancer is a disease that can arise from genetic mutations occurring within cells in the body— somatic cells (for soma, meaning body). Cancerous cells are aggressive in their attempts to grow and spread to places they are not meant without permission.
We all possess precancerous or slow-growing cancerous cells. In an autopsy study of six individuals, high rates of cellular mosaicism were found across different tissues. Mosaics were classified as having one or more large insertions, deletions, or duplications of DNA compared to the original ‘parent genome’ created at conception.
Mosaicism goes far beyond cancer. An increasing number of somatic mutations are being linked to other genetic diseases. These include neurodevelopmental diseases that can arise in prenatal brain formation and cause recognizable symptoms even when present at low levels. Brain malformations associated with these changes are linked to epilepsy and intellectual disability.
Humans can also be mosaics of ‘foreign’ genomes. Rare cases of confounded identities brought to light the first examples. In one case, a woman needing a kidney transplant did not genetically match her children; her kidney grew from the cells of her lost twin brother. In another case, the identity of a criminal was masked because cells from his bone marrow transplant had migrated into the lining of his cheek. Cheek swabs were taken for his DNA test. Even more remarkable, observations suggest that many women who have been pregnant might be genomic chimeras. In samples from brain autopsies of 59 women, for example, 63 per cent of neurons contained Y chromosomes originating from their male offspring (actually from the fathers).
Doctors and geneticists are just starting to explore what having a multiplicity of genomes means for human health. At this point they are busy mapping the extent of the phenomenon but the message is already loud and clear: genomics continues to astonish us and genomic diversity is appearing everywhere we imagine to look, including inside our own bodies.
Beyond genomics, epigenomics is perhaps an even higher mountain of diversity to scale. Genomes might be relatively static entities at the level of their nucleotides A, C, G, and T, but the double helix can be decorated in numerous ways that change how genes are turned on and off, and in which combinations.
In essence, exactly the same genome sequence can have very different effects depending on its history and context. Gene expression patterns can change frequently, and in some cases the modifications are even passed on to the next generation. It never ends. Human genetic variation continues to blindside us with its enormity and complexity.”
Field, Dawn; Davies, Neil (2015-01-31). Biocode: The New Age of Genomics (pp. 33-34). Oxford University Press. Kindle Edition.
I have a couple of concerns. Docs often don’t have enough time TODAY to get through an electronic SOAP note effectively, given workflow constraints. Adding in torrents of “omics” data may be problematic, both in terms of the sheer number of additional potential dx/tx variables to be considered in a short amount of time, and questions of “omics” analytic competency. To that latter point, what will even constitute dx "competency" in the individual patient dx context, given the relative infancy of the research domain? (Not to mention issues of genomic lab QC/QA -- a particular focus that I will have, in light of my 80's lab QC background).
President Obama’s current infatuation with “Precision Medicine” notwithstanding, just dumping bunch of “omics” data into EHRs (insufficiently vetted for accuracy and utility, and inadequately understood by the diagnosing clinician) is likely to set us up for our latest HIT disappointment -- and perhaps injure patients in the process.