Chromosome Substitution Strain Panel: A New Tool for Quantitative Trait Loci Analysis
JAX® NOTES Issue 493, Spring 2004
Many complex human diseases result from the interactions of multiple genes that contribute in a quantitative fashion to the overall disease phenotype. Identifying genes responsible for complex traits in humans is difficult. In mice, however, inbred strain crosses are available to facilitate identification of complex traits. Data from these crosses enables investigators to associate phenotype with loci that map to one or more regions on a particular chromosome. These genetic regions are called quantitative trait loci (QTL) and contain genes that contribute to disease. Identification of QTL is the first step in the process of associating a gene to a phenotype.
The recent availability of improved genetic markers [e.g. single nucleotide polymorphisms (SNPs)] allows researchers to map the location of QTLs more precisely and at a lower cost. In addition, mouse geneticists have created specialized sets of strains (recombinant inbred and recombinant congenic) that enhance complex trait analysis by improving the efficiency of identifying genes in mouse models of human disease. Despite these advances, QTL analyses in mice are time consuming and expensive, requiring large genetic crosses with extensive phenotyping and genotyping.
Chromosome substitution (CS), or consomic strains, can accelerate QTL identification and mapping. CS strains are produced by transferring a single, full-length chromosome from one inbred strain, called the donor strain, onto the genetic background of a second strain, termed the host strain, by repeated backcrossing. A set of 21 strains, each derived from the same donor and host strains, but having a different host strain chromosome (Chromosome 1-19, X or Y) replaced by its counterpart from the donor strain, comprises a complete panel of CS strains. The nomenclature used for the CS strains is as follows: Host Strain-Chr # Donor Strain/Laboratory code(s).
Dr. Joseph Nadeau from Case Western Reserve University developed the C57BL/6J-Chr #A/NaJ CS strain set by replacing individual chromosomes from the A/J donor strain in the C57BL/6J host strain. This set is particularly useful given the large number of phenotypic differences between JAX® Mice strains A/J (000646) and C57BL/6J (000664) inbred strains. These strains differ in their susceptibility or resistance to spontaneous diseases such as arthritis, asthma, atherosclerosis, and cancer. They also differ in susceptibility and resistance to a number of infectious diseases and in inflammatory responses. Moreover, they display significant physiological, behavioral, and sensory differences. The Jackson Laboratory is now distributing this panel of CS strains to the scientific community. Currently, 20 of the 21 C57BL/6J-Chr #A/NaJ CS strains are being distributed; the remaining strain will be released for distribution shortly (Table 1).
Table 1. Chromosome Substitution Strains from The Jackson Laboratory.
| Stock Number |
JAX® Mice Strain Name |
Standard Supply |
Stock Number |
JAX® Mice Strain Name |
Standard Supply |
| 004379 | C57BL/6J-Chr 1A/NaJ | Level 4 | 004390 | C57BL/6J-Chr 12A/NaJ | Level 4 |
| 004380 | C57BL/6J-Chr 2A/NaJ | Level 4 | 004391 | C57BL/6J-Chr 13A/NaJ | Level 4 |
| 004381 | C57BL/6J-Chr 3A/NaJ | Level 4 | 004392 | C57BL/6J-Chr 14A/NaJ | Level 4 |
| 004382 | C57BL/6J-Chr 4A/NaJ | Level 4 | 004393 | C57BL/6J-Chr 15A/NaJ | Level 4 |
| 004384 | C57BL/6J-Chr 6A/NaJ | Level 4 | 004394 | C57BL/6J-Chr 16A/NaJ | Level 4 |
| 004385 | C57BL/6J-Chr 7A/NaJ | Level 4 | 004395 | C57BL/6J-Chr 17A/NaJ | Level 4 |
| 004386 | C57BL/6J-Chr 8A/NaJ | Level 4 | 004396 | C57BL/6J-Chr 18A/NaJ | Level 4 |
| 004387 | C57BL/6J-Chr 9A/NaJ | Level 4 | 004397 | C57BL/6J-Chr 19A/NaJ | Level 4 |
| 004388 | C57BL/6J-Chr 10A/NaJ | Level 4 | 004398 | C57BL/6J-Chr XA/NaJ | Level 4 |
| 004389 | C57BL/6J-Chr 11A/NaJ | Level 4 | 004399 | C57BL/6J-Chr YA/NaJ | Level 4 |
Level 4: Up to 3 pairs or 6 individual mice can be shipped per order; 1 order at a time. Expected delivery for most strains is 1 to 3 months. Call to inquire about ordering greater quantities.
STATUS UPDATE:
C57BL/6J-Chr 5A/NaJ (004383) is currently available at Level 4.
Detection of a QTL associated with a phenotypic trait that differs between the donor and the host of a CS panel is accomplished simply by phenotyping mice from each member of the set. The presence of the trait of interest in a particular CS strain indicates that there must be at least one QTL on that chromosome. The advantages of QTL analysis using CS strains are that (1) initial linkage crosses are unnecessary, (2) genotyping is not required, (3) fewer mice need to be phenotyped, and (4) QTL with weaker phenotypic affects can be detected compared to results from linkage crosses. Mice of the CS strain exhibiting the trait of interest can be used to generate, within a few generations, a series of congenic strains that subdivide the chromosome into segments and thus refine the position of the causative locus. This process is achieved by backcrossing to mice of the host strain, identifying recombinant progeny, and determining which regions of the chromosome are associated with the phenotype.
References
(Authors in bold are Jackson Laboratory Scientists)
Nadeau JH, Singer JB, Matin A, Lander ES. 2000. Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221-5.
Fortin A, Diez E, Rochefort D, Laroche L, Malo D, Rouleau GA, Gros P, Skamene E. 2001. Recombinant congenic strains derived from A/J and C57BL/6J: a tool for genetic dissection of complex traits. Genomics 74:21-35.
Korstanje R, Paigen B. 2002. From QTL to gene: the harvest begins. Nat Genet 31:235-6.
Nadeau JH, Frankel WN. 2000. The road from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nat Genet 25:381-4.
Matin A, Collin GB, Asada Y, Varnum D, Nadeau JH. 1999. Susceptibility to testicular germ-cell tumours in a 129.MOLF-Chr 19 chromosome substitution strain. Nat Genet 23:237-40.
