The era of personal genomics is fast approaching, as headlines constantly remind us. With the cost of sequencing someone’s DNA rapidly falling toward just $1,000 (or less), it seems all but inevitable that soon we and our physicians will use that information to guide our health decisions.
But here’s an inconvenient biological truth that the triumphant talk about personal genomics sometimes skirts: we don’t each have just one genome. Yes, one may stand out most prominently for each of us, but we have others. And biology is still sorting out how much our health may depend on learning to pay attention to those we normally overlook.
All the cells in an organism like a human being certainly seem as though they should have the same genome. A fertilized egg divides repeatedly to give rise to the body’s cells, passing along the same set of chromosomes to every one of its cellular progeny. A few exceptional tissues might deviate from that rule — for example, red blood cells entirely discard the nucleus holding their genes, and the white blood cells called B lymphocytes scramble part of their DNA so that they can make an almost infinite number of different antibodies. But fundamentally, all the cells in the skin, the liver, the brain, the muscles and other tissues ought to share the same genome.
Or so it was thought. Yet exceptions to the rule keep cropping up, and they may help to explain some of the variation seen in tissues like the brain.
Variation on the brain
The hundred billion neurons in the human brain obviously differ from one another in their interconnections and in the specific neurochemical messenger molecules that they secrete. But a more subtle difference that has come to light over the past decade, largely thanks to the work of Michael J. McConnell and his colleagues at the Salk Institute for Biological Studies in La Jolla, Calif., resides in the DNA. They have shown extensive variation in the genomes of individual neurons, a condition called aneuploidy. The neurons have deleted, duplicated, and rearranged portions of their chromosomes, such that no two have exactly the same DNA sequence anymore.
Two weeks ago at the Society for Neuroscience meeting in Washington, D.C., McConnell presented the latest evidence that human brains are mosaics of genetically different cells. He and his coworkers took adult human cells and switched them into a more unspecialized, embryonic state — what biologists call induced pluripotent stem cells (iPSCs). They then coaxed the iPSCs to differentiate again into new adult neurons, and started comparing all the cells’ genomes.
They found a striking amount of variation. Not only did all the newly created neurons have different patterns of genomic deletions and duplications, but those patterns also differed from those of both their ancestral iPSCs and the original adult cells. The results suggest that the rejiggering of the DNA isn’t something that happens only early on, in versatile stem cells ancestral to neurons. Rather, the rearrangement of chromosomes is actually part of the cells’ normal development, and happens when they are well committed to becoming neurons.
Why brain cells would mix up their DNA in this way is still unknown. This genomic variation almost certainly causes individual neurons to behave slightly differently; it may therefore either help to explain the gigantic complexity already seen in the structure and function of the brain, or it may represent a whole additional level of complexity on top of it. Perhaps it accounts for why the distribution of neurological and behavioral responses so often follows a bell curve even in tightly controlled experiments — what neurobiologists have sometimes called the “intangible variance.” Or perhaps it helps to explain some of the differences in behavior and physiology that show up in studies of identical twins, who might otherwise be considered genetically identical.
In any case, the biomedical significance of this mosaicism in the brain could be considerable. Inherited deletions and repeats of certain genetic sequences cause many congenital problems, including neurological ones. Huntington’s disease, for example, is caused by dozens of extraneous repeats of a three base sequence in one gene, and the disorder called fragile X syndrome stems from too many repeats of one sequence on the X chromosome.
McConnell and others, however, have speculated that these more subtle rearrangements in individual neurons might also contribute to certain pathologies, such as schizophrenia, in people who might otherwise be considered to have normal genomes. If nothing else, the mosaicism could illuminate why finding a strong genetic basis for some of those conditions has been so difficult.
After all, as geneticists have known for decades, mosaicism affects the severity of symptoms from chromosomal abnormalities, such as Klinefelter syndrome (in which men have an extra X chromosome in addition to the normal XY pair) and Turner syndrome (in which women have only a single X chromosome). Some people who have these conditions manifest unusually mild forms of them, and in those cases, it often turns out that only some of the cells of their body actually have the irregular chromosome number. In them, the cell division error that caused the chromosome irregularity occurred after embryonic development had started, in just a subset of the cells.
All healthy women and other female mammals exhibit a form of mosaicism called X-inactivation. Although their cells carry two X chromosomes, early in embryonic development, one of the two is randomly and permanently turned off (which saves the cells from an overdose of the factors made by the X). Consequently, women’s bodies are a checkerboard of regions in which one or the other X is active. That pattern is visible to the unaided eye in calico cats, whose coloring is quilt-like because each copy of their X chromosome carries different fur pigments.
X-inactivation isn’t a true genomic mosaicism because the chromosomes in all the females’ cells are structurally the same. Yet women may commonly exhibit a more extreme mosaicism called chimerism as a side effect of becoming mothers.
Chimerism draws its name from the chimera monster of Greek mythology — part lion, part goat, part snake. In chimerism, an organism absorbs and integrates cells from another individual into its own tissues and accepts them as part of its body. Sometimes this can happen early in development, when two embryos accidentally merge into one.
Mother’s little helpers
But as studies make increasingly clear, chimerism also happens routinely, if limitedly, during normal pregnancies, too. As researchers discovered more than 30 years ago, at least a few cells from a fetus can sometimes make their way into its mother’s bloodstream and proliferate. In a case documented in 1996, a woman’s blood still contained fetal cells from her son 27 years after she had given birth. In 2010 researchers in China examining the brains of female mice reported finding many cells that had originated in the animals’ fetal offspring: in some brain regions, one in every 1,000 cells had come from fetuses.
Whether such fetal cells have an effect on their mother’s health, good or bad, has always been debated. But at least one recent study seems to support the hope that the fetal cells can sometimes come to the mother’s aid. Hina W. Chaudhry and her colleagues at the Mount Sinai School of Medicine reported in Circulation Research in November that when pregnant mice suffer a heart attack, circulating fetal cells with stem cell-like properties invade the damaged cardiac tissue and repair it. The fetal cells transform into a variety of more mature cell types that integrate themselves into the mother’s own tissues.
The full biomedical significance of mosaicism and chimerism won’t be known for a long time. But even if they turn out to be no more than footnotes in medical textbooks, they put the lie to the idea that each of us walks around with just one personal genome to consider. And these sources of variety don’t even begin to take into account the potential medical importance of the microbiome — the full complement of genes in the trillions of symbiotic bacteria, fungi and other organisms that live inside and on us, which are essential to our health.
Genome sequencing costs better keep falling. We’re going to need a lot of it.
Image: Microarray. (Credit: Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science. science.energy.gov/ber/)