The old cliché “two wrongs don’t make a right” proves true in many situations, but in the genetics of the brain, two genetic wrongs can make a right. A few years ago, I participated in research at Baylor College of Medicine (Houston, TX) in which we discovered that inheriting two different epilepsy-causing gene mutations can actually make an individual less epileptic.1 These findings provide evidence that God has built grace into our genomes. And not only is this grace representative of good design from an engineering standpoint, but it also reflects the character of God as our Creator.
Epilepsy is a chronic brain disease characterized by the repeated occurrence of spontaneous seizures. Although epilepsy can be acquired by brain damage such as head trauma, the disease is largely genetic, often caused by inheritance of multiple predisposing genetic risk factors. Of the more than a dozen genes known to underlie human idiopathic epilepsy (“idiopathic” means no known cause), almost all of them belong to a class of molecules called ion channels. In the brain, ion channels mediate signaling between neurons by regulating the flow of ions across the cell membrane. Studies in humans and mice have shown that individuals with more than one epilepsy-associated ion channel mutation usually have more severe seizures. However, since ion channels can have differing and often mutually opposing effects on neuronal signaling, my fellow researchers and I hypothesized that some combinations of ion channel gene mutations may actually exert mutually seizure-protective effects when present in the same individual. Such a result could explain the well-known sporadic nature of epilepsy in which the disease tends to skip generations despite the transmission of the epilepsy-associated mutation to the unaffected person.
In our study, we bred mice to carry two different gene mutations, both of which cause epilepsy independently. The first mutation disrupts a calcium ion channel gene (Cacna1a), causing mice to exhibit petit mal seizures, which are characterized by a non-convulsive, temporary cessation of activity. The second mutation deletes a potassium ion channel gene (Kcna1), causing mice to experience grand mal seizures, which cause severe shaking and convulsions. In addition, mice lacking Kcna1 die prematurely because of complications due to their severe epilepsy. When we examined mice carrying both the Cacna1a and Kcna1 mutations, they displayed a dramatic reduction in seizures and no longer showed the premature death characteristic of the Kcna1 mutation. These results demonstrate that in the appropriate genetic context, so-called “deleterious” mutations can actually be beneficial.
Although our study only pertained to a combination of two particular epilepsy genes in mice, evidence exists for “healthy” protective gene mutations in other human diseases. In studies of genetic risk factors for multiple sclerosis, a disease of the central nervous system, inheritance of certain gene variants (alleles) has been found to either confer disease susceptibility or protection. Whereas an allele called DRB1*15 is associated with a particularly high susceptibility to multiple sclerosis in carriers, four variants (DRB1*01, DRB1*10, DRB1*11 and DRB1*14) are linked to disease resistance, thus negating the harmful affects of the DRB1*15 variant.2,3 This principle of protective gene interactions is repeated again in age-related macular degeneration (AMD), where loss of vision in the center of the visual field (macula) leads to blindness. Studies looking for gene variants associated with resistance or susceptibility to AMD have found that not only do protective gene interactions occur at an appreciable frequency within the European-American population but also that the number of genetic combinations protective against AMD outnumber those linked to susceptibility.4, 5 Furthermore, the gene variants associated with resistance to AMD appear to exert protective effects of a magnitude comparable to that of disease-associated alleles (albeit in the opposite direction). Thus, although harmful mutations exist that can cause multiple sclerosis and AMD, beneficial mutations also exist that can counteract the deleterious ones.
Sequencing of the human genome also provides indirect evidence for the presence of protective gene mutations. Craig Venter, cofounder of Celera Genomics, recently published his own personal genome DNA sequence.6 Examination of his DNA revealed that Venter carries many gene mutations that put him at risk for a variety of medical conditions, including myocardial infarction (heart attack), coronary artery disease, hypertension, obesity, lactose intolerance, and Alzheimer’s disease. Although he may develop one of these diseases eventually, to date Venter has not suffered from any of these ailments. This incongruity may be a result of the action of protective gene mutations, which are counterbalancing his harmful mutations.
In reality, each of us almost certainly carries many potentially harmful mutations for which we will never suffer disease, partly due to environmental factors, but also at least in part due to the effects of protective gene mutations. An individual’s genome is estimated to carry a minimum of about 500 potentially damaging mutations.7 In addition, one to three new harmful mutations can be generated at each generation in each individual.8 If we have so many genetic strikes against us, why then are most of us relatively healthy, all things considered? Geneticists at Case Western Reserve University School of Medicine put forth the following hypothesis aimed at this question:
“A long and healthy life could result from fortuitous absence of disease causing genetic variants (winning Mendel’s lottery), from longevity genes or, more likely, from modifier genes and protective alleles in individuals with genetic and environmental disease risks.” 9
The God of the Bible is a God of grace and the existence of protective gene mutations provides evidence of this grace built into our genomes. The psalmist describes God as “compassionate and gracious, slow to anger, abounding in love. He will not always accuse, nor will he harbor his anger forever; he does not treat us as our sins deserve or repay us according to our iniquities. For as high as the heavens are above the earth, so great is his love for those who fear him…” (Psalms 103:8–11). The same God that does not treat us as our sins deserve also designed our genomes so that we do not suffer disease as we deserve.
That two harmful mutations have the potential to mutually cancel one another in some cases brings to mind the biblical story of Joseph in the book of Genesis. Joseph was sold into slavery by his jealous brothers and years later Joseph, who was then second-in-command to the Egyptian Pharaoh, had the opportunity to confront them and exact his revenge. Instead of getting even, Joseph shows them grace saying, “But as for you, you meant evil against me; but God meant it for good, in order to bring it about as it is this day, to save many people alive” (Genesis 50:20, NKJV). Similarly, harmful genetic mutations which are “meant for evil” can sometimes be used for good.
Dr. Glasscock received his Ph.D. from the University of California, Berkeley, and currently serves as Instructor of Neurology and Neuroscience at Baylor College of Medicine, Houston, TX.