We are involved in three major human disease gene studies. The first is the search for genes causing Alzheimer disease (AD). In particular, we are focusing on understanding the effects of the APOE gene on both early and late onset patients with AD. These studies involve genotyping both multicase families and isolated cases, and determining the risks for each APOE genotype. Additionally, we are studying the effects of other factors related to risk and APOE genotype, including disease onset, progression, duration, and gender. Although we know that APOE explains about 50% of all Alzheimer disease, it is clear that additional genetic factors are at work. We are currently using state-of-the-art laboratory and statistical techniques to genotype markers throughout the entire human genome for these factors.
Our second major disease gene search involves multiple sclerosis (MS). MS is a complex inherited disease where no simple mode of inheritance can be discerned. We are using newly developed (and constantly evolving) statistical techniques to analyze the genotypic data we generate across the genome. We are also using simulation studies to model the complex nature of MS and test various methods of analysis for their robustness and sensitivity.
Our third disease gene study involves mutational analysis of the tuberous sclerosis genes. We are currently using RT-PCR and SSCP to scan the TSC2 gene (mapped to chromosome 16) for mutations in both familial and sporadic cases. We are also matching the specific mutations we find to the specific disease expression in the patient with the goal of defining any genotype/phenotype correlations.
In addition to the above searches, we are involved in the genomic screening of six different Mendelian disorders (late infantile neuronal ceroid lipofuscinosis, LaFora Body disease, familial spastic paraparesis, familial dystonia, Crohn disease, and deafness). Once the disease genes have been localized through linkage analysis, we will apply positional cloning techniques to identify and clone the defective gene(s).
We are also studying various meiotic phenomena through sperm genotyping. Specifically, we are looking at the possibility of segregation distortion in specific diseases by genotyping sperm from affected males. In addition, these same data can be examined for individual variation in recombination, interference, mutation rates and the effects of age. These studies are likely to provide new insight into the biology of meiosis.