We normally think that every cell in our body contains the same genome, the complete set of genetic information that makes up the biological core of our individuality. However, there are exceptions where the body contains cells that are genetically different. This happens in cancers, of course, which arise when mutations create genetically distinct cells. What most people do not realize, however, is that the brain has remarkable genetic diversity, with some studies suggesting there may be hundreds of mutations in each nerve cell. In the developing brain, mutations and other genetic changes that occur while brain cells divide are passed down to a cluster of daughter cells. As a result, the adult brain is composed of a mosaic of genetically distinct cell clusters.
We know that the activity and organization of the brain changes in response to experience. Memories and learning are reflected in the number and strength of connections between nerve cells. We also know that the brain is genetically mosaic, but a new study makes a remarkable connection between experience and the genetic diversity of the brain. It suggests that experience can change the DNA sequence of the genome contained in brain cells. This is a fundamentally new and unexplored way in which experience can alter the brain. It is of great scientific interest because it reveals the brain to be pliable, to its genetic core, in response to the world.
The genome is the molecular signature of identity. The sequence of DNA contained in our genomes distinguishes each of us as unique individuals, and changes in that sequence are relatively rare. Genomic changes typically arise from rare errors during cell replication, or from exposure to carcinogens or radiation. Here, experience has an equally powerful capacity to change the genome, but only in cells of the brain. The care that a newborn receives in early life can have profound effects on psychological and intellectual growth. Attentive nurturing, feeding and grooming can reduce stress and anxiety and enhance psychological wellbeing. On the other hand, indifference can lead to increased anxiety and impaired psychological adjustment. This study reveals that one way the quality of early care could cause lifelong changes in behavior is by changing the brain’s genetic nature.
In this study researchers identified natural differences in the quality and abundance of maternal care provided by mice based upon measures of time they spent grooming and nursing their pups. They identified groups of animals that provided either high or low maternal care. They then examined brains of their pups for differences in markers of genomic change.
Many of the differences in the genomes of nerve cells are due to the presence of mobile genetic elements called retrotransposons. These are stretches of DNA that can be copied and, as the name suggests transposed or incorporated into other areas of the genome. This study measured the accumulation of these mobile genetic elements in the brain as a consequence of maternal care. Mobile genetic elements accumulated in specific regions of the brains of mouse pups if the pups had poor maternal care. If a pup was born to a mother animal that provided low maternal care, but raised by a mother animal that provided high maternal care that accumulation of mobile genetic elements was eliminated. This supported the idea that the accumulation of genetic elements was due to the care provided by the mothers rather than some inherited difference. Most of the excess was found in the hippocampus, a region of the brain involved in memory, but not in other regions of the brain, nor in a completely different organ like the heart, suggesting a very specific impact on brain mosaicism.
The authors also report that the changes in levels of mobile genetic elements might in turn be mediated by a modification to the genomic DNA known as methylation. Methylation is not itself a change in the DNA sequence, but it can alter when and how DNA sequences are read and utilized by the cell. Pups raised with poor maternal care had decreased methylation of key regulatory sequences in the mobile genetic elements which in turn led to increased numbers of these elements and increases in their activity.
There are important implications here. The augmented genomic variability among nerve cells may be beneficial to an individual by diversifying their behavioral repertoire. On the other hand, it may genetically predispose an individual to neurological or psychiatric disease even in the absence of any family history of such disease.
Gene mutations have long been known to cause brain cancers, but the effects of other genetic modifications such as those caused by mobile genetic elements are still emerging. There are a few examples of diseases caused by changes in the regulation of mobile genetic element number or activity. For example, Rett syndrome is an X-linked pervasive developmental disorder characterized by a spectrum of disabilities including abnormal behavior, speech and motor function. More recently, the mutations that cause some cases of ALS (Lou Gehrig’s disease) and frontotemporal dementia have been linked to the regulation of mobile genetic elements. These genetic alterations in the brain have such great potential as a source for insight into mental and neurological diseases that the National Institute of Mental Health established a research initiative, the Brain Somatic Mosaicism Network to investigate them.
Linking early experience to the genomic variability of nerves suggests that early experience leaves an irreversible genomic imprint in the brain. This is an intriguing new twist on a debate that has been raging for centuries concerning the importance of nature versus nurture in behavior. This study implies that nature and nurture are not as independent as may have been been imagined, and that nature is not as immutable as once thought. As with all iconoclastic studies, there are caveats to this research, most importantly the fact that the number of mobile genetic elements is much higher in the neurons of the rodents studied here than it is in humans. Furthermore, we don’t yet understand how these genetic changes alter the brain activities that give rise to behavior. Nevertheless, this is a provocative study that links early experience with the genetic structure of neurons, and that highlights the remarkable plasticity and adaptability of the brain.