Dear Students!
Our
next speaker on the 4th of April will be Seth Grant who will talk
about: "Madness, Genius, and the Origin of the Brain".
You
will need to read his papers titled:"The molecular evolution of the vertebrate behaviour repertoire" and "A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia"
Please post your comments not later than Tuesday (27th) afternoon!
Grant, S. G. N. (2016). The molecular evolution of the vertebrate behavioural repertoire. Philosophical Transactions of the Royal Society. Series B, Biological Sciences, 371(1685), 371.
ReplyDeleteFollowing the theory of evolution, humans present with a more complex behavioral repertoire compared to other vertebrates. Skene (2016) sought to identify the underlying mechanisms of diverse behavior in vertebrates to inform our understanding of how it evolved. It is believed that the evolution of synapses may be foundational in behavioral differences in vertebrates. Behavioral experiments following genetic engineering of synaptic mechanisms in mice and humans were used to model the synapse proteome expansion theory. These studies suggested synaptic expansion in genetic duplication, diversification, and constraint likely played a fundamental role in the evolution of cognitive complexity in vertebrates.
Question: Can you give more information on the function and role of a paralogue?
Skene, N. G., Roy, M., & Grant, S. G. N. (2017). A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia. eLife, 6, 1–30.
Transcriptome trajectory turning points (TTTPs) in genes can be used to identify trajectories for expression throughout the age span and potentially be used to identify the onset of disorders such as schizophrenia. Observations of similar TTTPs found in humans and mice indicate programmed brain gene expression in animals. TTTPs can also be used to inform our understanding of cellular process maturation and synaptic transmission across the lifespan in humans. Studying TTTPs in both neurological processes have indicated significant changes in young adulthood, a known onset time for schizophrenia. By applying a similar analysis of TTTPs to susceptible genes associated with schizophrenia, we can predict an approximate “enrichment” age window for onset, validated using various models and genetic datasets.
Question: Can you speak more to what is involved in transcriptomes? What are they used for, and could this be applied to other areas of the brain for assessing psychiatric disorders (i.e., outside of prefrontal cortex)?
The molecular evolution of the vertebrate behavioural repertoire
ReplyDeleteThis review describes the evolution of behavioral repertoires of organisms in terms of the “vertebrate expansion” of synapse proteome complexity. Under this theory, the synapse can be viewed as having evolved from unicellular organisms and plays a vital role in behavioral repertoire. Two whole genome duplications early in the vertebrate lineage drove an “expansion” in synapse protein complexity which yielded a broader behavioral repertoire as gene duplication allowed for increased diversity of specialized functions, regulation, and fine-tuning of behaviors. Behavioral mouse genetics and genetic engineering studies further support this theory by linking specific genes—or, more specifically, gene duplication and diversification—with simple and complex forms of learning. At the end of the article, Grant connects synapse proteome expansion with mental illness by acknowledging that such complexity in a behavioral repertoire is accompanied by susceptibility to disease-causing mutations, such as those linked with schizophrenia or autism.
A genomic lifespan program that reorganizes the young adult brain is targeted in schizophrenia
This study tracked age-dependent changes in gene regulation. Novel methods to detect changes in direction or plateaus of relative gene expression trajectories, known as Transcriptome Trajectory Turning Points (TTTPs), were applied across the lifespan to mouse and human brain tissue samples. TTTP occurrence tracked defining characteristics of gene regulatory events for both species at every age, creating a “genetic lifespan calendar” whereby the actual age of a tissue sample could be predicted with decent accuracy based on examination of an RNA sample. This genetic calendar induces important changes in synapse function that potentially shapes behavioral repertoire across the lifespan. TTTPs peaked in young adult humans around 26 years old and approximately 5 months old in mice where this peak was delayed for females in both species, underscoring the similarity of genomic program regulation of cellular and synaptic changes between mice and humans. Additionally, this dramatic reorganization of gene expression occurring around 26 years in humans (corresponding to the TTTP-peak), specifically relating to reorganization of synapse proteomes, is largely completed by around 40 years of age. The authors then propose that mutations of the genes that regulate transcriptome trajectories are likely responsible for several neurological and psychiatric diseases such as schizophrenia. Schizophrenia, they argue, is a genetic disorder that targets the mechanisms of brain aging (such as TTTPs) during young adulthood. However, TTTPs and the genetic calendar are not the answer for all disorders—high penetrance severe mutations will likely show an earlier onset and reduced dependence on TTTPs, and weaker alleles with subtle phenotypes at early ages may be exposed at later ages by changes in gene expression, such as with autism or intellectual disabilities. As this study was limited to prefrontal cortex transcriptome data, diseases with primary pathology in other areas of the brain, such as Parkinson’s disease, cannot be adequately assessed according to this genetic lifespan calendar, but that area remains an important expansion of this impressive work.
Approximately what percentage of diseases/disorders could be characterized by TTTPs, particularly if this work was expanded to encompass all brain tissues/regions?
Grant, S. G. (2015). The molecular evolution of the vertebrate behavioural repertoire.
ReplyDeleteGrant argues that the diversity and specialization of complex learning and behaviors in vertebrates is related to genome and gene duplications that increased the number and diversity of proteins involved in synaptic transmission. He views synaptic transmission as a processes with ancient evolutionary origins in unicellular organisms. Indeed the ways unicellular organisms interact with each other and their environment are reflected in the core features of synaptic transmission (e.g. membrane permeability and vesicles). Subtle differences between synaptic proteins can lead to a wide variety of behavioral differences. For example, variations of similar synaptic proteins structures in mice lead to differences in sensitivity to different frequencies in action potentials for long-term potentiation—with observable behavioral effects in learning rates and behavioral idiosyncrasies. Grant argues that the duplication of parts of the genome or genes responsible for encoding synaptic proteins allowed for the mutations in one duplicate to lead to a greater diversity of protein variants while a lack of mutations in another duplicate spared the original proteins from variation. Thus, new protein variants in genome duplicates had an additive effect to the number of diversity synaptic proteins—increasing the size and complexity of the synaptic proteome and leading to new opportunities for subtle specialization and the emergence of more complex behaviors.
Skene, Roy, & Grant (2017). A genomic lifespan program that reorganises the young adult brain is targetted in schizophrenia.
The authors present robust evidence from multiple techniques in mouse and human models to support the claim that the age of onset and sex differences associated with schizophrenia can be accounted for by changes in the life-span genetic calendar that regulates and changes the expression of genes associated with synaptic and cellular connectivity. The authors show that a variety of neurobiological processes follows a genetic calendar where their trajectory can plateau, increase, decrease, or change directions. These developmental trajectories are similar in both mice and humans and continue to change well into adulthood. The authors claim that the seemingly sudden onset of schizophrenic symptoms in early adulthood can be accounted for mutations in genes that regulate changes in synaptic organization in the pre-frontal cortex around this time. Their results were validated in both mouse and human models and were able to account for the 2-year delay in symptom manifestation associated with females.
Questions: This study was fascinating, I’m curious in could these neurodevelopment trajectories account for the critical period hypothesis associated with language development?
Through the discussion of previous genetic studies in humans and mice, Grant (2016) describes support for the theory of synapse proteome expansion which posits that expansion in the synapse proteome has led to the evolution of increased complexity within the behavioral repertoire of vertebrates. These complex behaviors include aspects such as sensations, memory, perception, reasoning, and emotions. It is suggested that genes derived from the same ancestral gene, or paralogues, may allow for the derivation of new functions and thus contribute to greater behavioral complexity in addition to gene duplication and its contributions to synapse proteome complexity. Overall, the discussed findings provide novel evidence regarding the underlying mechanisms of complexity and diversity in vertebrates and potential contributing factors for mental disorders within the human population.
ReplyDeleteSkene, Roy, & Grant (2017) use novel techniques to investigate the regulation of gene expression across the lifespan in both humans and mice. These techniques were used to classify and quantify the trajectories of gene expression based on the presence or absence of Transcriptome Trajectory Turning Points (TTTPs) as well as the trajectory direction following the TTTP if present. The results indicate that these trajectories can be used to characterize age of brain tissues and that enrichment of specific cell types within the brain (i.e., endothelial cells, microglia, pyramidal neurons, astrocytes) varies across the lifespan. This finding suggests that a “genetic lifespan calendar” exists which governs genetic expression across time. Upon further investigation, it was noted that TTTPs peak in humans at 26 years of age and 5 months of age in mice with this peak being slightly delayed in females. Furthermore, a significant reorganization of gene expression was noted around this TTTP peak. The authors suggest that mutations in genes during this reorganization and timing of TTTP peak may account for the onset of schizophrenia. However, it was noted that these findings cannot be directly applied to other neurological disorders as the collected samples were limited to prefrontal cortex and the affected regions for other disorders may demonstrate different transcriptome trajectories.
The molecular evolution of the vertebrate behavioral repertoire
ReplyDeleteIn this article, Grant discusses about the evolution in regards to the vertebrate growth within species and its affect on reflex and cognition. Behavioural repertoire represents use of individual behavioural components for adapting to the changes but the degree of adaption differs vastly between vertebrates and invertebrates. Vertebrates have shown to display a higher form of cognitive functions and reflexes when compared to invertebrates. An answer to the question involving a ‘higher’ evolution among vertebrates is explained through the behavioural experiments involving mice involving Dlg2 mutation which showed that rise in synapse proteome complexity and paralogues played a major role in diverse evolution among vertebrates. Grant also links the behavioural repertoire and synapse proteome expansion as a one of the important causes in the psychiatric disorders such as schizophrenia and autism.
A genomic lifespan program that reorganizes the young adult brain is targeted in schizophrenia
Brain profiling specifically transcriptome profiling across different ages can help reveal the complex changes in expression levels. Further, trasnscriptome trajectories can be used as a means to to predict age from tissue samples.Grant, in this paper, presents a methodology which helps in better understanding transcsptional events. Transcriptome Trajectory Turning Points (TTTPs) can be used to detect changes in gene expression trajectories. In schizophrenia, TTTPs predicted the onset age for schizophrenia to be around 22-26 years in susceptibility genes. The same test also resulted in displaying disparity in onset of schizophrenia between males and females by ~3-4 years.
The molecular evolution of the vertebrate behavioural repertoire
ReplyDeleteGrant (2016) provided an overview of the current literature regarding gene duplications in synaptic proteins. The overall goal of this work was to provide an evolutionary account for the shift from unicellular organisms to the specialization of diverse functions in humans and other vertebrae. The experiments reviewed assessed two gene families (e.g. NDMA receptor and Dlg/MAGUK) of scaffold proteins. The findings of the studies reviewed in this article provide a theory for the evolution of the behavioral repertoire and the underlying mechanisms. Moreover, Grant links the idea of synapse proteome expansion as potentially creating a sensitivity to mental illness.
I think I need a little more priming to really better understand this article. I get the overall goal of the research, but I am not versed enough in genetics to really grasp paralogues and diversification in gene regulation.
A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia
TTTPs helped to identify age-related gene regulatory events that were detected when the trajectory in gene expression levels changed. This study found that brain tissue could be used as a predictor of age by examining RNA. Skene et al. (2017) proposes a model or mechanism for the five central features of schizophrenia (e.g. genetic susceptibility, age of onset, sex differences, cell biological mechanisms and cognitive deficits). The authors suggest that transcriptome trajectories (TTTPs) cause a reorganization of the expression of synaptic proteins in young adults. Furthermore, these mutations cause issues with signaling that result in abnormal behaviors (i.e. those presented in schizophrenia). There is a strong relationship between schizophrenia and TTTPs.
Jessica Yoo
ReplyDeleteThe molecular evolution of the vertebrate behavioral repertoire (Grant, 2015)
Where do humans’ complex behavioral responses come from? The study reviews this question by reviewing the possible contributing mechanisms. Synapses have been studied to affect behaviors including cognition. Synaptic plasticity causes different synapses to influence different behavioral and electrophysiological levels. Grant and his colleagues came up with a theory that the expansion in synapse proteome play an important role in the advanced vertebrate behavioral repertoire, with the underlying idea that gene duplication leads to new functions (two gene families of the Dlg/MAGUK proteins and the GluN2 of NMDA receptor). Lastly, it is important to recognize that these expansions of synapse proteome become prone to mutations that contribute to schizophrenia and autism.
A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia (Skene et al., 2017)
With transcriptome trajectories, age onset and sex differences of schizophrenia can be predicted from tissue samples of human and mice studies. The method marks the changes in direction of a gene expression (TTTPs- Transcriptome Trajectory Turning Points). Skene explains the idea of a genetic lifespan calendar in humans and mice in regards to how it controls the brain cell types throughout different stages of ages. It was also found that a reorganization of the genes occurs at the start of the symptoms of schizophrenia, which shows the significant role this genetic lifespan calendar plays on the age of the occurrence of the disease. The changes in synapse proteome composition was found to arise at a young adulthood time frame. The proposed genetic calendar model of schizophrenia fulfills the 5 main features of schizophrenia in the genetic susceptibility, the age of onset, the sex difference, the cell biological mechanisms, the cognitive deficits, and therefore may be used to keep track of the onset of the disease. Can this model be used for diseases other than Schizophrenia?
The molecular evolution of the vertebrate behaviour repertoire
ReplyDeleteThe evolution of the sophisticated vertebrate behavioural repertoire has been explained by the importance of synapse proteome expansion. The behavioural repertoire (tries to answer "how did the vertebrate behavioural repertoire arise and evolve") was hypothesized to cause sets of individual behavioural features that unicellular organisms, invertebrates and vertebrates uses when adapting and responding to changes in its external world. The experiments on genome/gene duplication events showed the significance of comparative proteomic and genomic studies, led to identify the molecular origins of synapses in unicellular eukaryotes and the vertebrate expansion in proteome complexity. Also these molecular mechanisms play an important role for understanding the repertoire of behaviours in different species and for human behavioural disorders.
A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia
Again the genetic mechanism regulating the brain and behaviour across the lifespan were examined. Since growing ages go along with changes physically and intellectually, we are easy to develop mental disorders by certain ages. Symptoms for schizophrenia would occur with some signs of hallucinations, delusion or changes in behavior particularly in the mid-twenties. To understand these changes of genes in brain, the examination of genes turning on and off across the lifespan of healthy mice and humans were studied. The method of the transcriptome trajectories across the lifespan of the human neocortex and mouse hippocampus has been applied to identify the changes in the level of gene expression; by that age-dependent gene regulatory events were identified. Transcriptome Trajectory Turning Points (TTTPs) reached the peak at around 26 years old in young adult humans and approximately 5 months old in mice, with a delay in age for females. This peak also demonstrated a reorganization of expression of synaptic and schizophrenia susceptibility genes. Together with the TTTPs, the lifespan calendar studies helped predict the characteristic age of onset in young adults and sex differences in schizophrenia. The author suggested that the changes throughout the brains by age would be manipulated to help develop a new treatments for schizophrenia and other type of brain diseases.