Adaptive Evolution of Genes Underlying Schizophrenia
Bernard Crespi, Kyle Summers, Steve Dorus
The Royal Society
Biological Sciences
Nov. 2007 Vol. 274
Introduction
Schizophrenia afflicts close to 1% of the entire world’s human population. Recent theories, especially in the genetics field have begun to suggest potential resolutions to this mind crippling disorder. One evolving theory claims that “genetic liability to schizophrenia has evolved as a secondary consequence of selection for human cognitive traits”[1]. Recent studies have tested the hypothesis that certain schizophrenia-associated genes have been evolutionarily subject to positive selection. If this hypothesis proves correct then schizophrenia would technically “represent a maladaptive byproduct of adaptive changes during human evolution”1.
What is Schizophrenia?
When people think of this disorder, often times they think of John Nash’s disjointed conversations with invisible people about his paranoid delusions and his brilliant mathematical discoveries scribbled obsessively on dorm room windows. We often associate schizophrenia with pure and distilled insanity that at times can breed brilliance with the heavy price of social ineptitude. Schizophrenia literally means “split brain” which suggests a dissociation of what we consider “normally” integrated brain functions. The disorder is characterized by somatosensory delusions including visual and auditory hallucinations. This could include seeing things or people that aren’t there or hearing voices in one’s head or from the outside world. Some of the symptoms of schizophrenia include a loss of coherence and cogent thought with severe damage to logical cognition especially in language and appropriate social and emotional behavior. Though symptoms vary from case to case, the end results fall in the same category of extreme mental and social dysfunction.
Schizophrenia has a polygenetic basis, which involves numerous genes of small effect. “Phenotypic effects represent one end of a continuum that grades into schizotypal cognition and to normality” 1.
On a neurological level, there has been evidence in favor of schizophrenia’s effect on neuronal pathways, especially the neurotransmitter dopamine. “Increased dopamine activity in the mesolimbic pathway of the brain”[2] has been long associated with schizophrenia. In most cases, treatment for this disorder involves a drug therapy that decreases dopamine activity by blocking these receptors.
What is Positive Selection?
In the study we are reviewing it is crucial to understand what is meant by positive selection. As we delve into the world of genetic evolution, we see that certain genes have been historically either permanently integrated or weeded out of every species genetic makeup. When we talk about positive selection, it is referring to the fact that over a certain period of time, either spanning back to the earliest forms of sentient life or on a more recent time line specific genes have remained present, which suggests that the genes carry some adaptive quality in the furthering of the species’ evolution.
The Study
This study involved an analysis of the molecular evolution of 76 genes. The “criterion for inclusion of schizophrenia-linked genes was genetic association with the disorder via association studies (comparing allele frequencies or genotype distributions between cases and controls), or via family-based transmission–disequilibrium studies that test for differential inheritance of alleles between affected and non-affected siblings. We excluded all genes that were linked with schizophrenia in single studies, which were subject to failed replication attempts. The list of 76 such genes used here (electronic supplementary material) is highly congruent with that of Schmidt-Kastner et al. (2006) and was fully assembled prior to our analyses”1. They used two methods of measurement: a linkage disequilibrium-based method in order to test for evidence of recent selective sweeps which involves relatively large coding and non-coding genomic regions and a phylogeny-based maximum-likelihood method used for detecting positive selection based on ratio the ratio of non-synonymous to synonymous substitution rates (the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the amino acid sequence produced is not modified[3]). This method also takes into account the scientific philosophy that a hypothesis of any kind must reflect the most likely sequence of evolutionary events as DNA changes over time.
As we know, Schizophrenia is directed by many genes of small effect, which complicates the detection process by requiring extremely large samples.
Types of Analyses
Þ HapMap Analysis: recent positive selection is often detected through the identification of selective sweeps. Selection for a specific allele causes a relatively large block of surrounding DNA (extended haploytpe) to increase in frequency. A test has recently been developed that identifies selective sweeps using data from the human haplotype map. This HapMap is based on the human genome, which aids in the discovery of human genetic variations. In order to test for statistically higher indication of positive selection in schizophrenia-associated genes, this analysis compared the frequency of positive selection in the set of 76 genes previously selected with the same frequency in a set of 300 control genes.
Þ PAML Analysis: this level of analysis used orthologous mammalian genes sequences for human subjects. They tested codon and branch specific models (that represented periods when evolutionary changes appeared to spur the rise of schizophrenia) to identify the action of positive selection. This branch included human, basal-primate and human-chimpanzee lineages for each gene. For the detection of positive selection, they used Model A that identifies selection of specific codons along specific branches of the phylogenetic tree. Model A consisted of four categories of selection on codon sites in sequence W1=1, W0<1. If the maximum-likelihood resonated with a category of sites W<1 style="mso-spacerun: yes"> To test higher indication of positive selection in schizophrenia-associated genes, they compared the frequency of positive selection in the 76 genes with 120 control genes randomly chosen from the 300 from the HapMap analysis.
Results
Þ HapMap Analysis
14/76 genes showed significantly more signs of recent positive selection in comparison to the control genes
6/14 genes showed signs that the selection was localized specifically to the focal gene
4/14 genes showed signs of recent selection in more than one human population (the rest only in one population)
Þ PAML Analysis
4 genes: on human lineage
7 genes: earlier in human-chimpanzee lineage
11/76 schizophrenia-associated genes showed evidence for positive selection versus 10/120 control genes
Discussion
The results of this study strongly suggest that positive selection occurs more frequently in schizophrenia-associated genes than in control genes. Taking the maximum-likelihood method into account, it is clear that evolutionary changes are what brought this disorder into existence, and the evidence from this study suggests that it is evolution that is bolstering its genetic integration today. No ones is going to argue that this disorder is socially or neurologically adaptive; on the surface. Neurological research has determined that the areas of the brain that are most differentially dysregulated in schizophrenia include regions most subject to differential evolutionary change. “Positive selection for differential expression between humans and chimpanzees are differentially dysregulated in the dorsolateral prefrontal and orbitofrontal cortices of individuals with schizophrenia”1. This link between genetic favoritism and neurological functioning cannot be a coincidence. Previous studies have examined the correlations between schizophrenia-associated genes and creativity, imagination, creative and artistic skills and beneficial insight into problem solving. It appears that alleles of several schizophrenia-associated genes have a significant effect on these faculties. On a fundamental level, this cognitive association could begin to explain why genetically speaking, schizophrenia is adaptive.
Limitations and Implications
Þ The genes tested effect various other neurological, psychological and physiological conditions
Þ Controversy about what constitutes adequate statistical demonstration of association between allelic variations of a specific gene and schizophrenia
I wish I could say more about this presentation. I just can't wait to hear it explained during class because this is an area of great concern to me. I guess I want the meaning of the results broken down just a bit more. What's the significance of schizophrenia being an evolutionary disorder? Will new ways of treating it be put into affect because of this discovery?
ReplyDelete