Читать книгу Pathology of Genetically Engineered and Other Mutant Mice - Группа авторов - Страница 56

One variation of inbred mice is the creation of recombinant inbred (RI) mice. In this case, two different inbred strains are crossed to produce F1 progeny. As with creating inbred strains, breeding pairs of these F1 progeny are crossed to create an F2 population and then one pair is selected for breeding in this and each subsequent generation until at 20 consecutive generations of breeding (F20) from a single brother–sister pair a new inbred strain is created, which has approximately 50% of its DNA derived from each of the original parental inbred strains. The generation of many separate recombinant inbred strains from the same parental inbred strains creates a panel of recombinant inbred stains, each of which has an array of unique DNA recombinations and therefore unique subset of parental DNA segments. Recombinant inbred strains are named with a pair of 1‐ or 2‐letter strain abbreviation codes representing the original parental inbred strains (Figure 3.3) with the female founder strain first, followed by an X for the cross, then the male founder strain abbreviation followed by a slash, a number to indicate the specific line and then the laboratory code for who made the strain (Table 3.8). The higher the number of strains in a recombinant inbred panel, the potentially more valuable the collection due to the increased number of recombination sites available for comparison across the panel.

Table 3.8 Recombinant inbred and recombinant congenic strain designation.

BXD31/TyJ	AcB51/Prgs
B = C57BL/6J	A = backcross to A/J
X = cross	c = recombinant congenic cross
D = DBA/2J	B = C57BL/6J
31 = RI line number	51 = recombinant congenic line number
Ty = Lab that created the line (Benjamin Taylor)	Prgs = Lab that created the line (Philippe Gros)
J = Subsequent breeder of the strain, The Jackson Laboratory

The Jackson Laboratory Repository distributes more than 125 BXD RI lines and there are many more in private laboratories. Many of these BXD RI lines have been sequenced and annotated. Using websites, such as GeneNetwork (www.genenetwork.org) [15], it is possible to use these mice for localizing, if not necessarily identifying, the gene(s) responsible for a disease, response to a treatment, or for any phenotype observed in one of the parental strains but not the other. For example, if the primary gene responsible for a disease in DBA/2J mice is known, such as a hypomorphic allele of Abcc6 that causes pseudoxanthoma elasticum, and the gene is wildtype in C57BL/6J, by first identifying all the BXD lines that are homozygous for the D2 mutant allele, one can then select only those mice, phenotype them, and rapidly identify narrow genetic intervals from which to generate a small list of candidate disease modifier genes [16] (Figure 3.7). Other RI lines exist for a variety of crosses that can be used in a similar manner.

A variation on the RI line is the recombinant congenic strains that are created by crossing two inbred strains followed by one or several backcrosses to one of the parental strains. The resulting mice are then inbred without selection. Recombinant congenic strains are also named using 1‐ or 2‐letter strain abbreviation codes representing the parental strains, but a lower case c for congenic, not an X, separates them and the first strain listed is the host strain, that to which the backcrossing is done, and the strain symbol following the c is the donor strain, that contributing the least amount to the total genetic background. The AcB51/Pgrs recombinant congenic strain was generated by Dr. Philippe Gros by backcrossing (A/J x C57BL/6J)F1 to A/J for two consecutive generations then sibling inbreeding to generate a panel of recombinant consomics including this, line 51.