Genetic drift

Genetic drift is "...the constant tendency of genes to evolve even in the absence of selective forces. Genetic drift is fueled by spontaneous neutral mutations that disappear or become fixed in a population at random."

 

How genetic drift happens

Genetic drift in inbred mouse colonies happens slowly, subtly, and is difficult to detect and control. It is caused by the same factors (Bailey 1977; Bailey DW. 1982.  Immunology Today 3:210-14) that lead to substrain divergence:

  • Separation of a sub-colony from its parent colony for more than 20 generations (10 generations in the parent colony plus the 10 that simultaneously pass in the sub-colony)
  • Undetected spontaneous mutations that become fixed in a colony
  • Residual heterozygosity in or incomplete inbreeding of a colony before it is separated from its progenitors
  • Copy number variations (CNVs) (JAX® NOTES 2009)

Seven examples of genetic drift

  1. Genealogy of C57BL substrains - Click Image to view enlargement
    Figure 1. C57BL substrain divergence. At least 40 C57BL substrains develop between 1930 and 1970, some of which are due to genetic drift (adapted from Bailey 1977 by Dr. Michael V. Wiles, The Jackson Laboratory).
    Between 1930 and 1970, at least 40 C57BL substrains develop (Bailey 1977) — some due to deliberate outcrossing but most due to maintaining colonies separate from the originating colony for more than 10 generations (Figure 1)
  2. Histocompatibility variants (Bailey DW. 1982. Immunology Today 3:210-14) exist within A, AKR, BALB/c, CBA, C3H, C57BL, C57L, DBA, and WG strains
  3. Substrains C57BL/6N, C57BL/6Nmg, and C57BL/6JKun are phenotypically different from each other and from the C57BL/6J founder line (Sluyter et al. 1999)
  4. C57BL/6JOlaHsd, a substrain of C57BL/6J, has a spontaneous deletion encompassing part of the alpha-synuclein (Snca) gene and the entire multimerin-1 (Mmrn1) gene (Specht and Schoepfer 2004)
  5. A killer cell lectin-like receptor, subfamily D, member 1 gene (Klrd1) deletion on Chr 6 (Wilhelm et al. 2003) is identified in JAX® Mice strain DBA/2J
  6. A spontaneous deletion of two ion channel genes (Yang et al. 2003), Kcnq2 and Chrna4, in a C57BL/6J substrain generates a mouse model of epilepsy
  7. C3H/HeJ mice are homozygous for a paracentric inversion in Chr 6 (JAX® NOTES 2003)

Inattention to genetic drift can confound results

Inattention to the effects of genetic drift and substrain divergence can confound research conclusions, making them innacurate, misleading, and perhaps unusable. This risk is more than theoretical, as several examples have already been reported:

  • Wasted efforts because of a mix-up in AL/N substrains (Bailey DW. Immunology Today 1982; 3:210-14)
  • Confounded results due to lack of awareness of 129 substrains (Threadgill et al. 1997)
  • Dubious results because of inattention to C57BL substrain differences (Specht and Schoepfer 2001)

How many incidents have not been reported?

How we arrest genetic drift

  • We minimize the number of generations produced by breeder pairs in our foundation and production colonies
  • Highly skilled technicians oversee breeding in those stocks
  • Our patented Genetic Stability Program refreshes our foundation stocks with cryopreserved embryos or gametes about every five generations

Do your part to lessen the impact of genetic drift

  • Obtain mice from a reliable breeding source
  • If you maintain your own private colonies of these mice, periodically obtain new breeding stock from your supplier. Although colonies of inbred mice expanded from our breeding stock can be maintained either by sibling or non-sibling mating, they may develop into substrains if they are expanded beyond 10 generations
  • Avoid comparing results from substrains that either arose early in a strain's inbreeding regimen or that have been long separated
  • Use proper nomenclature to describe your mouse models
  • Include a detailed description of the genetic background of the mice you use in all your communications
  • When possible, use a common genetic background so that your experiments can be replicated