Hanley Kingston | Public Health Genetics

How Common Neurological Diseases Defied Basic Principles of Evolution, and the Theory that Fit it all Together

by Hanley Kingston | Apr 28, 2020 | Evolution

Main Takeaways:

Neurological diseases and disorders that strike during young age present some fascinating questions. 1) Is there a link between a genetic predisposition to these conditions and a propensity for genius or creative talent? 2) How have these often debilitating conditions remained so common, when many evolutionary models suggest the genetic risk factors for these diseases would have been eliminated through evolution?
New research shows that many early-acting hereditary neurological diseases are caused by similar types of genetic mutations. The occurrence of these mutations is common, but the exact location of each mutation can be unique to a small number of families. It is the commonality with which these mutations occur that explains the commonality of neurological diseases and disorders like schizophrenia, bipolar disorder, and autism, largely independently of the “genius connection.”
Humans may be unique in their propensity to develop such mutations.

The most basic principles of evolution dictate that serious genetic diseases that affect the young are rare because their sufferers are often less likely to have children and, therefore, less likely to pass along the disease-causing mutation(s). But common neurological diseases and disorders like schizophrenia, bipolar disorder, and autism long confused evolutionary geneticists by defying this principle. For instance, although most people with schizophrenia do not have children, the disease remains both highly heritable and common: striking about one in every hundred people.[1]

These conditions are fascinating, not only for their hard-to-explain abundance, but because of another well-known paradox – an apparent excess of savantism and creative genius among people affected by these neurological conditions, as well as among their family members. But while early hypotheses suggested that such cases might offer unique insight into the genetics and evolution of human cognition, the findings were often soured by preconceived notions about class and intelligence, from a 1970 study that observed that “close [male] relatives of psychotic individuals have a significantly increased probability of being considered persons of eminence” to more recent studies that crudely use occupation and college major as proxies for creative talent.[2]

Captivated by the possibility of a connection between genius and neurological disease, however, early research proposed that a long-understood evolutionary phenomenon called balancing selection, might explain the commonality of schizophrenia and autism. In balancing selection, inherited parts of the DNA that cause disease in some people are able to last throughout many generations by benefiting others. Sickle Cell Disease is a well-known example. People who have two copies of a mutation in the hemoglobin-beta gene (one from each parent) suffer from the life-threatening disease. People who carry just one copy, on the other hand, have few of the associated negative health effects but do have enough of the sickle-shaped blood cells to make their blood resistant to infection by malaria-causing parasites. By affording resistance to a different disease, the mutation for sickle cell increases its own odds of making it into the next generation and bucks the forces of evolution that would otherwise largely eliminate it. The authors of the 1970 study on schizophrenia and eminence postulated a very similar mechanism – the existence of at least one genetic mutation that could cause schizophrenia in people who inherited it from both parents but which increased creative talent in people who inherited only the one copy.[2]

As genetic causes of many diseases were solved through advanced genetic techniques, however, it became clear that most neurological diseases were not quite like Sickle Cell Disease in that not everyone with the disease had a mutation in the same gene. In fact, very few common diseases, neurological or otherwise, can be explained by the same mutation in each person.

Most common diseases are caused by a combination of many common variations between different people’s DNA (termed genetic variants).[3] Everyone carries around some pieces of DNA that increase their risk of diseases and others that decrease their risk. In certain families and, therefore, certain individuals, the risk-increasing pieces for a given disease are especially common, and they are more likely to develop the full-blown disease. This is the genetic mechanism that best explains asthma and cardiovascular disease and has proven roughly accurate to explain late-onset neurological conditions like Parkinson’s and Alzheimer’s. Because Parkinson’s and Alzheimer’s usually occur in late adulthood, however, they have little effect on the likelihood of having children and their commonality is not paradoxical, as it is for diseases like schizophrenia, where we would not expect harmful variants to persist throughout generations. Among other popular explanations, we return to balancing selection, which can also apply to diseases caused by multitudes of common variants if the common variants are beneficial to the people who dodged the full-blown disease. The variants, scattered throughout the genome, are hypothesized to act like vitamins or drugs: they’re helpful, to a point – but detrimental in too high a dose.

Balancing selection explains many aspects of human physiology, but as an explanation of the persistence of common neurological disorders, the theory has recently suffered several major blows. Most seriously, there is little indication that genius of any variety yields any advantage from an evolutionary standpoint. Selection depends on the number and health of your children and is largely indifferent to Who Is Who lists.[4] This does not mean that the “mad genius” connection is not real or that it has nothing to tell us about the evolution of the human brain; recent research suggests that the link between schizophrenia and creativity, if present, has been overblown, but there’s likely some link between bipolar disorder an IQ and savantism, while rare, is overrepresented in autistic individuals.[4,5,6,7,8] While modern research remains mixed on whether there is a connection between neurological disorders and specific skillsets, it is almost definitely not the driving force behind the prevalence of these diseases.

Recent research finally explains common neurological conditions in a way that is consistent with long-established principles of evolution. Like sickle cell disease, these conditions are often caused by a single mutation in each person, but unlike sickle cell disease, it is not the same mutation in each person.[9] Like a boat flooding as fast as it is bailed out, every generation, new mutations pop up randomly in different spots in different unlucky people.

The impact of common rare mutations is not unique to neurological disease. Cancer-stricken families are often uniquely unlucky in that the mutations they share are very uncommon outside of their family, although hereditary cancers as a whole are sadly abundant. Medical practice is just starting to recognize the importance of considering these distinct mutations in classifying and treating cancers. Similarly, Schizophrenia disease-causing mutations are scattered throughout the genome, yet they cluster by the types of biological pathways they fall into.[9] Similarly, researchers have been able to subclassify cases of autism – a hugely broad umbrella diagnosis – by their rare mutations, finding subsets of ten or twenty patients from around the world who share the same mutations and who show pronounced similarities in appearance, mannerisms, and health.[10] These studies are also resolving a third paradox of neurological disease – a tendency for families to experience high levels of more than one prognostically distinct neurological disease. It turns out that the genes in which the disease-causing mutations occur are often the same genes that give rise to mutations causing other neurological conditions like depression, bipolar disorder, autism, epilepsy, and schizophrenia.[ 11,12]

On its face, this conclusion seems less than extraordinary: neurological disorders are common because our brains are complex and typical function depends on a large percentage of our genes working properly; however, this simple finding has much to teach us about the evolution of the human brain.[9] How did humans get to be so sensitive to these mutations? Our genome may be uniquely fragile. While humans are not special in our number of genes – we have fewer than some fleas – we are unique in the number of segments in our DNA that have nearly exact copies in separate parts of our genome. Certain areas of the genome are hotspots for co-opting these duplicated segments and occasionally merge them into novel genes. Creating new “patchwork” genes in this way may have given us a cognitive edge over other primates; however, the consequence of having parts of our genome that almost exactly match other parts is that sometimes the replication machinery in the genome gets confused between the two regions and causes errors, like failing to copy part of the DNA or copying a part too many times. These errors can result in both common and rare diseases that are often neurological in nature.[13,14] The errors that occur between duplicated regions look distinct from the types of errors that cause diseases like sickle-cell or the genetic variants that increase the risk of Alzheimer’s disease. This new research suggests neurological diseases may be a price we pay for evolving the most advanced brains in the animal kingdom.

References:

How Common Neurological Diseases Defied Basic Principles of Evolution, and the Theory that Fit it all Together

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