Although rodent crosses have been immensely important in helping scientists dissect the underlying mechanisms of complex human diseases, they have limitations. The most important one is poor resolution: Because the quantitative trait loci (QTLs) revealed by rodent crosses generally contain hundreds of genes, identifying the specific alleles that underlie a disease phenotype is quite difficult. To produce a tool that can reveal QTLs with fewer genes, a team of 37 scientists led by Anatole Ghazalpour, Ph.D., from the David Geffen School of Medicine, University of California, Los Angeles, developed the hybrid mouse diversity panel (HMDP). The panel consists of some 114 inbred mouse strains – all available from The Jackson Laboratory – and can typically resolve QTLs to less than a megabase (usually less than five genes) (Ghazalpour et al. 2012). Along with other mouse panels, such as the Collaborative Cross and consomic strains, the HMDP will greatly facilitate identifying disease alleles and the development of new disease therapies.
Key features of the HMDP
To develop a panel that captures loci with effect sizes typical of mouse complex traits, the Ghazalpour team used an association-based approach corrected for population structure and supplemented with recombinant inbred (RI) strains. They selected mouse strains that can increase genetic mapping resolution, are renewable and available to investigators worldwide and can contribute data that can be shared and integrated among genomic, transcriptomic, metabolomic, proteomic and clinical phenotypes. The HMDP core panel consists of 29 classic parental inbred strains. Closely related strains and wild-derived strains are not included. The genetic diversity lost by not including wild-derived strains is offset by better statistical power. The statistical power is also increased by the inclusion of RI strains and can be further increased by including data from other crosses and RI strains.
Because so many single nucleotide polymorphism (SNP) genotypes are known among the HMDP strains, genotyping is unnecessary.
The HMDP is particularly suited for systems genetics and for analyzing genetic interactions. Unlike the progeny of a genetic cross, the HMDP can be used to characterize an unlimited number of phenotypes, gene interactions and epistatic interactions.
The HMDP has already been successfully used to identify several complex trait genes and/or their functions. Following are a few examples:
- To identify complex trait genes: e.g., that the Asxl2 gene influences bone mineral density (BMD) in both humans and mice (Farber et al. 2011)
- To identify gene mechanisms: e.g., that Asxl2, at least partly, influences BMD by regulating osteoclastogenesis (Farber et al. 2011)
- To identify gene networks: e.g., those associated with conditional fear (Park et al. 2011)
- To investigate relationships among different biological scales: e.g., among liver phenotypes, transcript levels and proteins (Ghazalpour et al. 2011)
- To develop a multi-scale understanding of a number of complex traits (more than 70 clinically relevant traits reported so far): e.g., elevated heart rate (Smolock et al. 2012)
The Systems genetics resource database
Researchers can integrate and analyze HMDP data via the Systems Genetics Resource (SGR) database. The SGR contains mouse genomic, transcriptomic, metabolomic, proteomic and clinical trait data from the HMDP, some traditional mouse crosses and some human studies. The data are accompanied by detailed descriptions of how they were collected, protocols and links to relevant published papers.
The SGR can be queried for gene and trait correlations, gene expression or QTLs. Data can be downloaded to perform various types of analyses, answer questions and understand the relationships among different genes. For example, the Ghazalpour team used the data to determine that the interferon inducible helicase 1 (Ifih1) gene interacts with the environment and is controlled by bacterial lipopolysaccharide (LPS). They also found that its expression is controlled by three loci on Chrs 5, 8, and 13 and were able to compare its expression patterns among different tissues. The SGR has facilitated their ability to identify candidate regulators, examine gene-by-environment interactions and tissue specificities and prioritize candidate genes (Ghazalpour et al. unpublished).
As data accumulates, the power of the SGR will expand. Some HMDP and other complex trait data are available in the GeneNetwork, Mouse Genome Informatics and Mouse Phenome databases.
Improving HMDPs power
Although the HMDP's resolution is excellent, its power is not. However, it can be enhanced by integrating its data with that from other crosses or by including more inbred and RI strains, such as the 62 advanced intercross RI lines in the new LXS (a.k.a. ILSXISS) panel, 50 new BXD strains, 19 cryopreserved AKXD strains, 13 cryopreserved AKXL strains and 15 cryopreserved NXSM strains – all available from The Jackson Laboratory. Such strains can expand the HMDP panel to more than 260 strains. Recombinant inbred congenic, consomic and Genome Tagged Mice (Peters et al. 2007) can also be added. As mentioned earlier, HMDP data can be integrated with that from other panels, notably the Collaborative Cross.
In summary, the HMDP will enable researchers to more quickly and efficiently identify disease alleles, detect gene-gene and gene-environment interactions, identify epistatic interactions and understand gene functions without the perturbing influences of transgenes and gene targeting. Researchers will be able to perform all these tasks more quickly, with fewer resources, and without genotyping.