Disrupted in Schizophrenia 1 (DISC1 Gene): Hodgkinson et al., 2004

While searching for an article to explain pleiotropy and how it interacts with epigenetics, I came across an article about the proposed ideas of the genetics behind Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder. This article caught my attention as it shows a current example of how genes affect our phenotypes and the types of research being undertaken in order to understand what the source of many diseases are. There is some mention of pleiotropy in the article, but I will go into more detail on that subject next week. For this week, I will try to explain what was found in the study of the Disrupted in Schizophrenia 1 (DISC1) gene.


Hodgkinson et al. (2004) believe that Schizophrenia and Bipolar Disorder are inherited and that there is a specific gene locus responsible for these psychiatric diseases. Specifically, the DISC1 gene is thought to undergo recombination causing a change in expression (Hodgkinson et al., 2004). The DISC1 protein is involved with many other proteins which causes this single gene to play a role in cellular processes that regulate neuronal signals and gene expression (Hodgkinson et al., 2004). Any alteration to the function of this gene is believed to have a pleiotropic effect on the individual. Depending on how the gene function is altered, there could be many different associations with the other proteins that DISC1 interacts with (Hodgkinson et al., 2004). The result of such a shift may be observed through different phenotypes seen in people with Schizophrenia, Bipolar Disorder, or Schizoaffective Disorder. These disorders may be a result of single-gene pleiotropy where there are different changes in the sequence of a gene or they may be from single-locus pleiotropy where there is a common change in the sequence (Hodgkinson et al., 2004). The type of alteration leads to different phenotypes which can be observed in the various symptoms experienced by individuals affected by these disorders. Hodgkinson et al. (2004) also found that reduced activity of the DISC1 gene between exons 1 and 9, coupled with environmental conditions may also be a source of the psychiatric disorders discussed in the article. The recombination of DISC1 gene was not found to be the key factor in these disorders, although evidence demonstrated that it did result in depression (Hodgkinson et al., 2004). Hodgkinson et al. (2004) did find that an amino acid substitution in the haplotype causes a change in protein structure that seems likely to result in Schizoaffective Disorder. They also believe that such changes may cause a decrease in transcription of the DISC1 gene that could also result in a psychiatric disorder (Hodgkinson et al., 2004). Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder are believed to be linked by the DISC1 gene, and the variation of changes to this gene are the cause of the different phenotypes associated with each of the diseases (Hodgkinson et al., 2004). These disorders are still under study, but it appears that genetics play a major role in each of these cases.

Summary: Feinberg (2007)

Last week, I discussed the role of epigenetics on gene expression and how this resulted in differences in phenotype. The example of the flowering plant demonstrated an epigenetic adaptation that promoted survival for the organism, but alterations to gene expression aren't always beneficial. Feinberg's (2007) research provides evidence that epigenetics can also lead to disease and possibly cancer. There is a possibility that certain histone modifications affect the way genes are regulated and cause changes in gene expression and function (Feinberg, 2007). This can prevent phenotypic plasticity from occurring normally and results in the cells' inability to modify behaviours based on input from environmental factors (Feinberg, 2007). Cancer is thought to be a result of both a change in the frequency of DNA methylation and other histone modifications (Feinberg, 2007). The decrease of methylation in tumours results in the activation of many growth-promoting genes, like HPV16 of the human papilloma virus which greatly influences cervical cancer (Feinberg, 2007). While some genes are being turned on by loss of DNA methylation, other genes are being turned off by an increase in DNA methylation. As tumour suppressor genes are silenced, genes such as RB in retinoblastoma, can no longer due their job thus allowing the development of cancerous tumours (Feinberg, 2007). Research suggests that progression of cancer in organisms may be a result of other chromatin modifications (Feinberg, 2007). In lymphoma and colorectal cancer there is a histone modification (Feinberg, 2007). Histones play an important role in the packaging of DNA so that different genes can be expressed or silenced. The expression of genes is observed through the phenotype of organisms. The particular modification in lymphoma and colorectal cancer is a missing H4 acetylated Lys-16 and trimethylated Lys-20 which is believed to cause silencing in transcription (Feinberg, 2007). The way these modifications affect whether certain genes are expressed or how they are able to function greatly impacts the response on the cells of the organism. In the examples from Feinberg (2007), these small changes have huge impacts on the organism. Without the normal regulation of genes, cancer and other diseases may result due to the cells' inability to respond to their changing environment.


Reference:
Feinberg, A 2007, 'Phenotypic plasticity and the epigenetics of human disease', Nature, vol. 447, pp. 433- 440.

Summary: Jaenisch & Bird (2003)

Phenotype is a result of the genotype, but we always seem to focus on the observable differences between organisms rather than digging deeper to understand how they all come to be. Epigenetics plays a major role in gene expression and in turn causes differences in organisms' phenotypes. The nucleotide sequence of DNA remains the same, but the way the gene acts is modified (Epigenetics Group- Garvin Institute of Medical Research, 2010). These modifications affect the expression of the gene, either silencing it or turning it on (Epigenetics Group- Garvin Institute of Medical Research, 2010). We can see the differences in gene activity by the varying characteristics or behaviours that correlate with each gene modification. Sometimes epigenetics occurs by chance while other times it is a response to the environmental setting (Jaenisch & Bird, 2003). This ability to adapt to environmental stimuli demonstrates that epigenetics is a dynamic process. Gene modifications aren't permanent and may change depending on different situations and factors (Jaenisch & Bird, 2003). The regulation of one gene can have multiple implications, as many genes normally interact to accomplish a task. The change in expression of one gene can either inhibit or allow another gene to activate which leads to differences in the phenotype. Once the activity of a certain gene is altered, this new arrangement can be passed down to the offspring of that organism (Jaenisch & Bird, 2003). As a result, new phenotypes may evolve and lead to new populations of species as time passes. One form of epigenetics that is believed to silences the expression of targeted genes is called DNA methylation (Jaenisch & Bird, 2003). Jaenisch and Bird (2003) observed an example of DNA modification in plants that grow in high altitudes. Sometimes these plants experience the urge to flower earlier because of the cold temperatures with which they live in (Jaenisch & Bird, 2003). The Flowering Locus C (FLC) gene is thought to be the gene which reacts to the cold environment, causing flowering to occur prematurely (Jaenisch & Bird, 2003). The combination of DNA methylation and expression of an inhibitory gene (VRN2) silences the FLC gene so that the plant won't flower at the wrong time (Jaenisch & Bird, 2003). In this circumstance epigenetics was able to take environmental factors into account and alter gene expression in a way that the organism was able to better survive. This is only a brief example of the influence of epigenetics on genes. It has many other applications in different species which are currently still being researched. 

Unless you are an identical twin, have you ever seen anyone else that looks exactly like you? Even as a twin, there are noticeable differences between the two people. How can this be possible while still sharing so many of the same genes? There is variation within every species as the genetic makeup of each organism influences the different phenotypes that we are able to observe. It isn’t as simple as just having a set of genes that correspond to a certain phenotype though. Genes provide the framework and ability to possess certain characteristics, but the real question is what genes will be expressed and to what extent they will be expressed. Phenotypes are at the mercy of the regulatory processes of genes. Each individual may possess some genes that aren’t regulated, and if they aren’t turned on then they will never be expressed. Only expressed genes will result in visible traits in an organism. As organisms evolve, we are able to observe changes in morphology, physiology, and behaviours. These adaptations don’t just appear in the phenotype, but have to start at the genes themselves. We always refer to natural selection as a tendency towards a specific trait, but we should really look deeper and find the root of these changes. Associate Professor Peter Dearden, Director of Genetics Otago, (Genotype/ phenotype connection, 2011) has done research on the matter, and believes that genes may not actually be the initial source of evolution. From his research, he concluded that the way genes interact with one another may be changing and this is what results in the differences in gene expression (Genotype/ phenotype connection, 2011). Barrier et. al (2001) have also compared evolutionary changes in phenotype to the genetic makeup of organisms. They believe that regulatory genes may be the source of such noticeable changes in organisms (Barrier et. al, 2001). With these findings, it appears that the focus shouldn’t necessarily be on the different genes an organism has, but rather how each of the genes they do have function and how this corresponds to different phenotypes.

 

References:

Barrier, M, Robichaux, R, Purugganan, M 2001, ‘Accelerated regulatory gene evolution in an adaptive radiation’, PNAS, vol. 98, no. 18, pp. 10208-10213.

The genotype/ phenotype connection 2011, Science Learning Hub- The University of Waikato, viewed 6 March 2014, <http://www.sciencelearn.org.nz/Contexts/Uniquely-Me/NZ-Research/The-genotype-phenotype-connection>.