Sex-restricted non-Mendelian inheritance of mouse Chromosome 11 in
the offspring of crosses between C57BL/6J and (C57BL/6J ×
Jay Shendure,* Justine A. Melo,* Kara Pociask, Rachel Derr, Lee M. Silver
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544-1014, USA
Received: 19 December 1997 / Accepted: 10 June 1998
Abstract. We report on the observation of sex-restricted, non-
Mendelian inheritance over a region of mouse Chromosome (Chr)
11, occurring in the offspring of crosses between two commonly
used Mus musculus-derived inbred strains, C57BL/6J and DBA/2J.
In the surviving backcross progeny of reciprocal matings between
(C57BL/6J × DBA/2J)F
hybrids and the C57BL/6J parental
strain, we observed the preferential appearance of C57BL/6J al-
leles along a region of Chr 11. The deviation from Mendelian
predictions was observed only in female offspring from both re-
ciprocal backcrosses, and not in males from either cross. The sex-
specificity of the observed non-Mendelian inheritance points to an
explanation based on embryonic or neonatal lethality. Our data add
to previously obtained evidence for a Chr 11 locus or loci with
sex-specific and allele-specific effects on viability.
The first law of genetics developed by Gregor Mendel states that
alleles at a locus will segregate equally to offspring of a hetero-
zygous parent. In recent years, however, various examples of
‘‘non-Mendelian inheritance’’ have been uncovered. Based on cur-
rent biological understanding, there are three situations in which
allelic frequencies in the population of surviving offspring could
deviate significantly from a one-to-one ratio.
The first is classical segregation distortion, in which the de-
parture of allelic frequencies from an even ratio is a consequence
of unequal meiotic segregation in a heterozygous parent. An ex-
ample of this phenomenon is provided by the segregation distor-
tion observed from females of wild Mus mus musculus populations
that are carriers of an aberrant form of Chr 1 (In/+; Agulnik et al.
1990; Ruvinsky 1995). During meiosis, the aberrant Chr 1 is pref-
erentially transmitted (∼85%) to the secondary oocyte and then to
the egg (rather than to either polar body), leading to distorted
allelic frequencies in the female animal’s offspring.
The second situation is a consequence of post-meiotic, but
pre-fertilization effects on gamete functionality. A well-studied
example of this phenomenon is the t-haplotype system on mouse
Chr 17 (Silver 1985). Spermatids bearing the variant t-haplotype
form of this chromosome post-meiotically inactivate their wild-
type competitors and, as a consequence, gain a relative advantage
in fertilizing ability (Silver 1993).
The third situation is a consequence of post-fertilization effects
with the differential survival of embryos, neonatal progeny, or
newly born pups that carry a particular allelic combination at a
particular locus. An example of this phenomenon is the ‘‘DDK
syndrome,’’ in which an incompatibility between DDK maternal
cytoplasm and non-DDK alleles at a Chr 11 locus (Om) leads to
differential embryonic survival (Babinet et al. 1990; Sapienza et al.
1992; Renard et al. 1994; de Villena et al. 1996). When DDK
females are crossed to (C57BL/6 × DDK)F
males, the inheritance
of the C57BL/6 allele at the Om locus is semilethal at an early
embryonic stage, leading to the preferential appearance of the
homozygous DDK genotype at Om in the population of surviving
offspring (Sapienza et al. 1992).
It is difficult to estimate the frequency with which any of these
types of non-Mendelian inheritance occur in even the best-studied
animal species, because none produces a visible phenotype that
can be readily interpreted. Nonetheless, through the process of
performing whole-genome scans in the pursuit of unrelated goals,
numerous examples of non-Mendelian inheritance in the mouse
have been uncovered. In particular, through the course of various
interspecific backcross matings between animals of the murine
species, Mus musculus musculus and Mus spretus, non-Mendelian
inheritance has been observed on regions of Chr 2 (Siracusa et al.
1989, 1991), Chr 4 (Ceci et al. 1989), Chr 10 (Justice et al. 1990),
and Chr X (Biddle 1987; Montagutelli et al. 1996). Several of
these reports (Siracusa et al. 1991; Biddle 1987; Montagutelli et al.
1996) proposed sex-specific differences in allelic transmission ra-
In the study reported here, outcross-backcross matings between
closely related members of a single species, the Mus musculus-
derived C57BL/6J and DBA/2J inbred strains, were used to gen-
erate several hundred second-generation animals. Incidental to the
mapping of loci affecting alcohol consumption levels (Melo et al.
1996), genotypic analysis of the N2 population led to the obser-
vation of female-specific, non-Mendelian inheritance along a re-
gion of Chr 11.
Materials and methods
C57BL/6J (B6), DBA/2J (DBA), and (B6 × DBA)F
animals were pur-
chased from The Jackson Laboratory. N2 animals were bred at Princeton
University from reciprocal matings between B6 and F
animals. N2 ani-
mals were weaned at 3–4 weeks. For all crosses described in the text, the
convention of placing the maternal strain to the left of the cross sign and
the paternal strain to the right is followed.
Genomic DNA was prepared from tail and spleen tissues according to
standard protocols. Primers purchased from Research Genetics (Huntsville,
Ala.) were used to PCR amplify microsatellite markers as indicated by the
manufacturer (Dietrich et al. 1994). When possible, markers were selected
with large differences in size between B6 and DBA products so that typing
could be performed by ethidium bromide staining. When necessary, mark-
ers with product size differences of less than eight base pairs were analyzed
P-labeled primers, and product was separated by electrophoresis on
denaturing gels. All data input and analysis was performed with the Mi-
crosoft Excel software package on the Macintosh computer.
* These authors contributed equally to this publication.
Correspondence to: J. Shendure at Suite #104, 33595 Bainbridge Rd.,
Solon, OH 44139, USA
Mammalian Genome 9, 812–815 (1998).
© Springer-Verlag New York Inc. 1998