VANCOUVER, British Columbia - Interest in founder populations has been renewed as a result of the explosion of molecular biological techniques and the initiation of the Human Genome Project.
Founder populations are ideal for sorting out the genetics of complex disorders because of their relative genetic homogeneity. The goal is to use founder population genetics to identify and characterize mutations that give rise to specific disease phenotypes.
Two papers delivered at the Human Genome meeting (HGM 2000) held here last week demonstrated this fact.
Michael Hayden, senior scientist and director of the Centre for Molecular Medicine and Therapeutics in Vancouver, reviewed work on the genetic contributions to HDL cholesterol levels in the general population using the families originating from different founder populations. Low HDL levels represent the most frequent lipoprotein abnormality associated with premature atherosclerosis. Despite its recognition as an important risk factor, there are few therapeutic options that reliably and reproducibly raise the level of HDL levels in humans. In an effort to understand the genetic concomitants of the disorder, Hayden's group has adopted a high-throughput genomics approach to identify novel genes.
Use of multiple founder populations allows the determination of different haplotypes overlapping minimal genomic segments, which result in more rapid determination of a minimal genomic segment of limited physical distance, thus facilitating high-throughput screening and identification of putative genes.
Disturbances in HDL metabolism have been defined as those associated without cholesterol efflux. Families with low HDL levels and cholesterol efflux abnormalities have been shown to have mutations in the ATP-binding-cassette (ABC1) gene. This gene codes for the cholesterol-efflux regulatory protein (CERP). These include families with Tangier disease as well as familial HDL deficiency. In addition, other families have now been identified that also have efflux abnormalities, but clearly by segregation analysis and multiple recombinants do not match to the ABC1 locus, so other important genes must be involved in determining cholesterol efflux in humans.
The researchers hope that their findings will eventually lead to therapies that will elevate HDL in patients.
In the second paper, Tom Hudson, a genome scientist who helped establish the Genome Centre at McGill University in Montreal, also reviewed genetics research in a Canadian founder population. His group has been working with Quebec's French Canadian population, one of the better-known founder population models used in research, looking at the genetics of relatively complex disorders such as asthma, diabetes and coronary heart disease. This is because of the relative genetic homogeneity stemming from the group's uniquely French Catholic ancestry and its cultural isolation up until the 1950s.
This large population base of 6 million individuals arose through rapid expansion (large families) from relatively few founding families and is comprised of several very large extended families. The genealogical records of the population are intact and were recorded by parish officials. Linkage disequilibrium (LD) studies such as those traditionally performed within families can be effectively scaled up in founder populations.
In relatively young founder populations, haplotype segments shared between individuals still are relatively large even after 12 generations. The large population base also ensures the number of meiotic steps between two "unrelated" individuals is large enough for fine-mapping studies in a relatively homogenous genetic background.