Thursday, June 27, 2013

Autism and Genetic Mutations

Autism spectrum disorders (ASD) is a general term that encompasses a group of disorders that have as their point of origin anomalies in the development of the human brain.  The neurological symptoms that have been associated with ASD include: impairment of normal social development, difficulties with verbal and nonverbal communication and marked repetitive behaviors.  In terms of the latter symptom, anomalies in the brain circuits that are also implicated in obsessive compulsive disorder (OCD) have been identified.  The syndromes that fall within the general definition of ASD include autistic disorder, Rett syndrome, childhood disintegrative disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS) and Asperger syndrome. Paradoxically, certain individuals sometimes display uncanny abilities in visual skills, music, math and art.

In general, the disease is discovered in young children, usually between 2 and 3 years old.  ASD has been diagnosed in over 2 million individuals in the U.S. and many millions throughout the world.  Evidence obtained through the statistics compiled by the Center for Disease Control (CDC) indicates that the incidents of ASD are increasing.  The reasons for this are unclear.

What has been ascertained is that there is strong genetic component in this disease.  What makes ASD particularly refractory to the development of a definitive cure is that the molecular biology is quite complex and involves a multiplicity of genes.  In this report, the findings of Dr. Brian J O’Roak and his colleagues, from the Department of Genome Studies at the University of Washington in Seattle and other collaborating institutions, will be examined.

Autism spectrum disorders (ASD) is a general term that encompasses a group of disorders that have as their point of origin anomalies in the development of the human brain.  The neurological symptoms that have been associated with ASD include: impairment of normal social development, difficulties with verbal and nonverbal communication and marked repetitive behaviors.  In terms of the latter symptom, anomalies in the brain circuits that are also implicated in obsessive compulsive disorder (OCD) have been identified.  The syndromes that fall within the general definition of ASD include autistic disorder, Rett syndrome, childhood disintegrative disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS) and Asperger syndrome. Paradoxically, certain individuals sometimes display uncanny abilities in visual skills, music, math and art.

In general, the disease is discovered in young children, usually between 2 and 3 years old.  ASD has been diagnosed in over 2 million individuals in the U.S. and many millions throughout the world.  Evidence obtained through the statistics compiled by the Center for Disease Control (CDC) indicates that the incidents of ASD are increasing.  The reasons for this are unclear.

What has been ascertained is that there is strong genetic component in this disease.  What makes ASD particularly refractory to the development of a definitive cure is that the molecular biology is quite complex and involves a multiplicity of genes.  In this report, the findings of Dr. Brian J O’Roak and his colleagues, from the Department of Genome Studies at the University of Washington in Seattle and other collaborating institutions, will be examined.

In this exhaustive study, samples from 2446 ASD patients were used.  Of the 192 candidate genes, 44 genes were selected.  This selection was based on the determination to look at disruptive mutations, known associations with ADS-related symptoms, overlap with genes known to be involved in neurodevelopment and gene copy number variation (CNV).

A summary of the results of this work follows –
  • Discovery of 27 de-novo genetic mutation events in 16 genes
  • 59% of these mutations predicted to either shorten the protein gene products or disrupt the splicing that is required to yield functional protein products
  • Recurrent disruptive mutations in six genes – CHD8, DYRK1A, GRIN2B, TBR1, PTEN AND TBL1XR1.  Five of these genes are contained within the catenin-chromatin-remodeling network.

This data confirms associations with specific genes and particular phenotypic expressions of ASD – CHD8 has been linked to macrocephaly and DYRK1A with microcephaly.  In addition, these results confirm the possible role of the catenin-chromatin-remodeling network - a critical network of genes and gene products involved in embryonic development.  However, these data do not establish an unambiguous causal relationship between these genetic anomalies and ASD.  This work represents an important contribution in the search for such direct causal link that may eventually lead to therapeutic relief for individuals with ASD.

Monday, June 17, 2013

Alternative Genetic Splicing – What is its Significance?

There exists a seeming paradox among the many species that constitute vertebrates – animals with backbones.  The fact is that although so many of these species share similar families of protein-coding genes, they are very distinct in terms of their physical characteristics – their phenotypes.  There is no clear explanation of how this phenomenon can be defined on the molecular level.

What has been well established is the fact that over the evolutionary time scale for these various species – approximately 350 million years – significant changes have occurred in their respective transciptomes.  A transcriptome represents the entire set of all RNA molecules within a cell including Messenger RNA (mRNA), Ribosomal RNA (rRNA) and Transfer RNA (tRNA) and the so-called “non-coding” RNA.  It can either be used to represent the complete set of transcripts for an entire organism or for a particular cell type – for a particular organ, for example.  The transcriptome, in essence, is a quantitative measure of the genes that are actually being expressed at any given time and as such can very dependent upon the particular set of environmental conditions that the organism is subjected to.

From the accumulated data, it seems unlikely that changes in gene expression can account for the diversity of characteristics found among members of the vertebrate family.  It seems more likely that changes in alternative splicing (AS) may be responsible for the species-specific differences found in nature.  AS is a process in which a single gene can, in fact, result in the production of more than one protein.  This is a regulated process that determines what exons – that portion of a gene that that has coding information for the final protein product - will be included or excluded in the final m-RNA.  It is this mechanism that accounts for the fact that far more proteins are produced from the ~ 20,000 protein-coding genes found in the human genome than would ordinarily be expected.

Given these assumptions arrived at from well-supported evidence, Dr. Nuno L. Barbosa-Morais and colleagues, from the Banting and Best Department at the Donnelly Centre of Medical Research at the University of Toronto, Canada, conducted a genome-wide investigation of AS differences among equivalent organs from vertebrate organisms encompassing all vertebrates higher on the evolutionary scale than fishes – tetrapods.  The organs that they used for the investigation were whole brain, forebrain cortex, cerebellum, heart, skeletal muscle, liver, kidney, and testis.  This approach engendered a significant amount of precise and demanding work

From this exhaustive study, they found significant differences in the complexity of AS between the various lineages studied with the highest complexity found within primates.  The species examined spanned ~ 350 million years in the evolutionary time scale.  Furthermore, within 6 million years the splicing patterns of the individual organs studied diverged to the extent that they were more closely correlated with the identity of the species than to the organ type.

These results add significantly to the understanding of the underlying genetic mechanisms that account for the diversity of characteristics found within the vertebrate family of organisms.


Wednesday, June 5, 2013

The Relationship between Obesity and Insulin Resistance

Metabolism – the sum of all the chemical reactions in the body necessary for sustaining life - and immunity – the ability of the organism to defend against threats posed by the invasion of microorganisms such as bacteria and viruses – are intimately linked in the biology of mammals. It is this relationship that allows the organism to adapt to changes in both the internal and external environments. However, within the modern western diet and lifestyle that promotes the development of obesity, this close association of metabolism and immunity can have deleterious consequences. Through the evolutionary history of the human species, humanity has had to survive in the face of the possibility of death as a result of starvation, infection and predation. It is only relatively recently in human societal development that such threats have been significantly lessened due to the introduction of agriculture to meet the nutritional needs of human populations and significant progress in technology and medicine. These age-old threats have been supplanted, however, by new concerns regarding individual mortality posed by cardiovascular disease, diabetes and cancer. The evidence now strongly indicates that obesity is an essential component of these troubling diseases. Between 1980 and 2008, the total number of obese individuals has essentially doubled worldwide to .5 billion individuals and the global death rate attributed to obesity is currently at ~ 3 million people per year. Drs. Justin Odegaard and Ajay Chawla from the Cardiovascular Research Institute at the University of California at San Francisco have examined the “cellular and molecular connections between chronic low-grade inflammation, insulin resistance and obesity-induced metabolic disease.” The focus for this report will be on the relationship between obesity and insulin resistance. Within this context, obesity can be defined as an imbalance between caloric intake and energy expenditure – calories in/calories out. This state of imbalance leads to the storage of excess nutrients in white adipose tissue (WAT). For lean individuals this imbalance is readily compensated by metabolic adjustments in WAT, liver and skeletal muscles. However, in a state of chronic over-nutrition, these pathways are overwhelmed leading to wide-ranging intracellular and extracellular dysfunction. Although these deleterious effects are the result of complex metabolic processes, the end product of these disturbances leads to the inhibition of insulin signaling – insulin resistance - through the modification of the insulin receptor substrate resulting in diabetes. In addition, the metabolic stress responses that are a product of chronic obesity, leads to the triggering of the innate immune receptors resulting in inflammation. This is, indeed, troubling data especially in regards to global public health. It appears that chronic over-nutrition is a cause for concern since the health ramifications that result from obesity have a major impact on individual quality of life and mortality.