2014 : WHAT SCIENTIFIC IDEA IS READY FOR RETIREMENT?

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Gary and Mary West Endowed Chair of Innovative Medicine; Professor of Genomics, The Scripps Research Institute; Author, The Creative Destruction of Medicine
One Genome Per Individual

We were taught that the fertilized egg divides to ultimately yield a human being---recently estimated to have ~37 trillion cells—each with the same, authentic copy of one's genome. Unfortunately that simple, seemingly immutable archetype just got mutated.

While there started to be questioning of the classical teaching—one genome per individual—decades ago, it was only recently through our newfound capability of performing single cell sequencing and high-resolution array genomic hybridization that this was unequivocally debunked. For example, in 2012 it was reported that the brain cells from 59 women had Y-chromosomes in 63% of them. Many found that hard to accept. But recently researchers at the Salk Institute did single cell sequencing of post-mortem human brain neurons and found that a striking proportion of the cells (ranging up to 41%) had structural DNA variants. This level of so-called mosaicism in the brain was far greater than anticipated and brought up the question as to whether our single cell sequencing technology might have some flaws that account for the observation. That doesn't appear to be the case, however, as too many independent studies have come up with a similar finding, whether it is in the brain or other organs, such as skin, blood or the heart. This year, a group at Yale found that a high fraction of kids with congenital heart disease carried mutations not present in either parent, perhaps accounting for 10% of severe heart disease birth defects.

These spontaneous "de novo" mutations of cells in the course of one's life are a curve ball for geneticists who thought that heritability was a generation passed down story. More reports of sporadic disease keep popping up, attributable to these de novo mutations, such as amyotrophic lateral sclerosis (Lou Gehrig's disease), autism, and schizophrenia. The mutations can occur at many time points along the human lifespan. A sample of 14 aborted human embryos in development showed that 70% had major structural variations, even though this would not be representative of live births. At the other end of the time continuum, in 6 people who died, unrelated to cancer, there was extensive mosaicism across all organs assessed, including liver, small intestine and pancreas.

But we still don't know if this is merely of academic interest or has important disease-inducing impact. For sure the mosaicism that occurs later in life, in "terminally differentiated" cells, is known to be important in the development of cancer. And the mosaicism of immune cells, particularly lymphocytes, appears to be part of a healthy, competent immune system. Beyond this, it largely remains unclear as to the functional significance of each of us carrying multiple genomes.

The implications are potentially big. When we do use a blood sample to evaluate a person's genome, we have no clue about the potential mosaicism that exists throughout the individual's body. So a lot more work needs to be done to sort this out, and now that we have the technology to do it, we'll undoubtedly better understand our remarkable heterogeneous genomic selves in the years ahead.