BoneKEy-Osteovision | Commentary
Genetics of osteoporosis: Of mice and men
DOI:10.1138/2001051
The past few years has seen an explosion of interest in the genetic determinants of bone disease and much of this work has focussed on osteoporosis. Osteoporosis is a difficult disease to study from a genetic viewpoint because it is complex condition which is caused by an interaction between several environmental factors and a multitude of different genes. Many approaches have been used to identify the genes responsible for osteoporosis in man, including studies of candidate genes in unrelated individuals and linkage studies in families or sib-pairs (). Another approach which has become increasingly popular is to conduct genetic mapping in experimental animals. Most of this work has focused on the identification of chromosomal regions (quantitative trait loci; QTL's) that regulate bone mineral density (BMD) () but other traits such as bone fragility, bone regenerative capacity and trabecular microstructure have also been successfully mapped ().
Initial detection of QTL's has mostly been achieved by genetic mapping studies in the progeny of crosses between two inbred mouse strains. The procedure, as applied to the detection of BMD QTL's, involves crossing one inbred mouse strain which has low BMD with another mouse strain which has high BMD (). The resulting offspring (the F1 generation) typically have BMD values between those of the parental strains because each mouse inherits a set of low BMD alleles from one parent and a set of high BMD alleles from the other parent. The next step is to intercross the F1's with one another, or backcross the F1's with one of the parental strains to create a second generation (F2). These mice have varying levels of BMD, ranging from low to high, because of recombination between the parental alleles and segregation of these alleles in the offspring. By genotyping the F2 generation of mice and correlating genotype with phenotype, it is possible to identify regions of the genome (QTL) that segregate with BMD and hence show evidence of linkage to BMD.
Another approach is to analyse BMD in recombinant inbred (RI) strains of mice (). The RI strains are derived from the F2 generation of an inbred strain cross by carrying out further brother x sister matings for several (>20) generations. As the result of this breeding program, RI mice develop fixed recombination points between the parental chromosomes and become homozygous for alternating stretches of chromosome derived from one or other parental strain. Any variation in BMD between the different RI strains is due to inheritance of QTL's that regulate BMD. Detection of these QTL's in RI mice also depends on conducting a genome-wide scan and correlating genotype with phenotype, but many RI strains - including those used by Klein and colleagues () - have already been extensively genotyped for multiple genetic markers, allowing investigators to conduct a genome wide search in silico and assign QTL's by simply looking at genotype data held on existing databases ().
Whatever method is used, mouse linkage studies generally result in the identification of a large chromosomal interval (10-30 cM) which must be narrowed down to have a reasonable chance of identifying the gene or genes responsible. The usual strategy employed is to create congenic strains through repetitive backcrossing (). This technique helps to pinpoint specific regions of interest, and can facilitate the identification of the functional gene within a QTL. The development of congenic strains involves transfer of a chromosomal segment from one strain onto the genetic background of another (background) strain. By genotyping a segregating population of animals for two markers flanking the QTL of interest, and breeding mice heterozygous for those markers back to a progenitor strain, a small segment of DNA containing the QTL of interest is gradually moved with each succeeding generation into the inbred progenitor background. The production of congenic strains requires some time and effort, but the payoff is enormous since the influence of an individual QTL on any trait can be tested by comparing the congenic with the background strain at any level from the molecular to the physiological.
A novel approach to reduce the critical region in QTL's recently employed by Klein and colleagues takes advantage of the fixed recombination between parental alleles which exist in RI strains (). This strategy, termed RI segregation testing (RIST) (), employs a RI strain which possesses a crossover (recombination point) within the QTL of interest to generate two F2 populations - one with each parental strain. By using linkage analysis, to determine within which of the two genetically heterogeneous populations phenotype segregates with genotype, the QTL can be mapped to either above or below the recombination point and successive iterations of this strategy can be used to narrow the QTL to a smaller and smaller chromosomal region (Figure).
Using both of the approaches outline above, investigators in the bone field have begun to fine map many QTL's that regulate BMD in different mouse strains (). Does this work have relevance for understanding the genetic basis of osteoporosis in man? The answer is that it probably does, at least in part. Several of the mouse QTL's for BMD identified so far are conserved between different mouse strains and also overlap with corresponding (syntenic) regions of the human genome identified as regulators of BMD by linkage studies in man (). Since most human linkage studies are not adequately powered to detect loci of modest effect, regions of the human genome which are syntenic to the mouse linkage QTL's represent attractive areas in which to search for positional candidate genes that regulate BMD using sensitive techniques for gene identification such as linkage disequilibrium mapping ().
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