The identification of susceptibility genes and phenotypic subgroups for autism spectrum disorders

Autism Spectrum Disorders (ASDs) are characterized by impairments in social interaction and communication, as well as restrictive behaviours and interests. These life-long disabilities affect more than 1 in 250 individuals. It has been shown that early diagnosis is essential for children with ASD: the earlier intervention is initiated, the better the outcome. However, affected children are commonly not definitively diagnosed until they are three years of age or older. Sibling, twin and family studies have shown that ASDs are largely genetic in origin and certain chromosomal regions harbouring possible ASD susceptibility genes have been identified. Recent studies suggest that between 5 and 48% of individuals with autism exhibit chromosomal anomalies. This suggests that small chromosomal anomalies, such as microdeletions and microduplications, may be relatively common and clinically important markers for identifying underlying causes of, and susceptible gene regions for, ASDs. Dr. Suzanne Lewis is researching the genetic susceptibilities of ASD, using a novel method for the analysis of regional changes in DNA called microarray-based comparative genomic hybridization (array-CGH). Using this method she is identifying and characterizing chromosomal abnormalities in 100 subjects with ASD. In parallel, Dr. Lewis is also researching ASD phenotypes – genetic influences in combination with respective behavioural, physical, medical, environmental and family findings. Dr. Lewis aims to build a research pathway that identifies genetically distinct subgroups of ASD that also share unique clinical phenotypes. Through researching this genotype/phenotype correlation Dr. Lewis ultimately hopes her research will contribute to a better understanding of the genetic causes and consequences of autism and help in developing methods for the very early identification of infants and families at risk for autism.

Creation and function of neighborhoods in eukaryotic chromosomes: regulation by SWR1-Com, a desposition complex for histone variant H2A.Z

Chromatin is the complex of DNA and protein material that make up chromosomes, home to the genetic code. The basic unit of chromatin is the nucleosome, a fundamental building block consisting of DNA wrapped around an octamer of histone proteins. A large number of proteins involved in cancer development and the genetic susceptibility to devastating diseases such as Ataxia Telangiectasia (a progressive immunological and neurological disorder) act through modification of chromatin structures and interfere with normal chromatin function. Differences in chromatin structures between adjacent regions specify the properties of larger macrodomains called neighbourhoods. The shape and structure of these neighbourhoods influence chromosome behavior, while complex regulatory mechanisms that ultimately involve chromatin ensure that each cell expresses only the appropriate genes, duplicates its genome with high fidelity, divides only when required, all while combating constant assaults on its DNA. Failure in any of the mechanisms regulating these events can lead to disease. These chromatin structures themselves can also be inherited, creating an additional complex set of influences that are crucial for the identity and activity of the cell. The molecular biology of chromatin structures and their role in chromosome biology and genome function in health and disease is the focus of Michael Kobor’s research. Specifically, he is studying a unique chromosomal neighbourhood containing a specialized histone variant known as H2A.Z, which is deposited into chromatin by a large protein complex. Using innovative genome-wide approaches, Dr. Kobor’s team aims to uncover the rules and principles of histone variant function.

An investigation into priority setting by hospital formulary committees in British Columbia: what weight does evidence carry in the face of competing factors?

Some health care services are prioritized at the expense of others, due to limited resources. Many decision makers set priorities for allocating resources based on evidence derived through health economics and clinical research. The trend towards evidence-informed health policies has gained considerable momentum in Canada, particularly with pharmaceutical policy because drugs are a major cost driver in the health system. It is clear, however, that health policies are not determined solely on the basis of health research evidence. Kristy Armstrong is examining the roles played by evidence and other factors — such as an institution’s values, and the interests of key stakeholders — during decision making about drug coverage in both a regional health authority and a hospital in British Columbia. This study will help clarify the environment in which health policy is set and potentially point to ways of more effectively integrating use of evidence in decision making.

Protein and lipid transport in health and disease: molecular mechanisms of endocytic sorting

Lysosomal storage diseases involve an inherited enzyme deficiency caused by genetic defects. Every cell has hundreds of lysosomes, which contain digestive enzymes used to break down complex cell components such as proteins into simpler components for the cell to reuse. In lysosomal storage diseases fatty substances called sphingolipids accumulate inside brain cells and cause progressive neurological degeneration and early death. Potentially, a lack of digestive enzymes may be the root cause. Recent research also suggests that the way the brain transports cholesterol may contribute to the damage associated with these diseases. The Saccharomyces cerevisiae yeast uses genes that are similar to those found in humans to control the transport of proteins and fats inside the cell. Dr. Elizabeth Conibear is identifying these genes in yeast and in mammalian cells. The research could help reveal ways to change the transport and storage of cholesterol and other lipids, which could lead to methods of preventing accumulation of fatty substances in the brains of children with these diseases. Developing a better understanding of how the cell transports cholesterol could also have important implications for treating adults with heart disease.

The early external cephalic version 2 trial

Of almost 40,000 babies born in BC in 2002, nearly 2,000 (4.8 percent) were breech (their bottom and legs were born before their heads). Research shows that breech babies are most safely delivered by Caesarean section. However, Caesareans cause more complications than vaginal births, and the resulting scar on the uterus complicates subsequent pregnancies. When a baby is found to be in a breech position using ultrasound, care providers can try to turn a baby to a head down position by feeling the baby through the mother’s abdomen and moving the baby’s head downward and its bottom upward. This procedure is called external cephalic version (ECV), and studies have shown that the chance of both breech birth and Caesarean section is reduced if ECV is performed close to the end of pregnancy (after 37 weeks). Dr. Eileen Hutton and her team of researchers from across Canada are conducting The Early ECV 2 Trial, which is an international randomised controlled trial designed to investigate whether performing ECV earlier in pregnancy, at 34-35 weeks, further decreases the number of Caesarean sections without increasing the risk of preterm birth. Dr. Hutton, founder and editor of the Canadian Midwifery Journal of Research and Practice, is also involved in a large international trial investigating the best way for twins to be born (vaginally or by Caesarean section), and is doing work in BC investigating patient initiated Caesarean section.

Nutrition Research Program

Dietary components are powerful determinants of health, affecting every aspect of human function from regulation of gene function to growth, physical and cognitive performance as well as our susceptibility to and ability to recover from disease. The Nutrition Research Centre at the Child and Family Research Institute on the site of BC’s Children’s & Women’s Health Centre is exploring the development of innovative nutritional strategies for preventing and managing disease, and for supporting children to achieve their maximum potential for physical and neurological development and health throughout life.

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Intestinal innate immunity: recognition and response to enteric bacterial pathogens

Bacterial infections of the gastrointestinal tract are very common, particularly among children. These infections cause diarrheal outbreaks and millions of deaths worldwide. Bacteria are also a major problem in Canada, with BC having one of the highest rates of intestinal bacterial infection in the country. Bacteria are believed to trigger a variety of gastrointestinal diseases, including inflammatory bowel disease, a debilitating and chronic condition that affects one in every 1,000 Canadians. Despite the prevalence of bacterial pathogens (disease-causing organisms), little is known about how the immune system recognizes and combats intestinal bacterial infections. This information is important because the immune response to these bacteria determines who is susceptible to infection, as well as the severity of the resulting disease. Dr. Bruce Vallance is researching how bacteria cause intestinal disease and how the immune system identifies and fights these infections. Dr. Vallance is investigating whether genetic differences in hosts influence susceptibility to food and water-borne bacteria. He aims to identify immune responses and genetic factors that either protects against intestinal bacteria or causes susceptibility to infection. This research could help explain how bacteria cause intestinal disease and ultimately lead to new treatments to prevent both bacterial infections and bacterial-induced gastrointestinal diseases.