- Research article
- Open Access
Measurements of hybrid fertility and a test of mate preference for two house mouse races with massive chromosomal divergence
© The Author(s). 2019
- Received: 16 October 2017
- Accepted: 10 December 2018
- Published: 16 January 2019
Western house mice Mus musculus domesticus are among the most important mammalian model species for chromosomal speciation. Hybrids between chromosomal races of M. m. domesticus suffer various degrees of fertility reduction between full fertility and complete sterility, depending on the complexity of the chromosomal differences between the races. This complexity presents itself in hybrids as meiotic configurations of chromosome chains and rings, with longer configurations having a stronger impact on fertility. While hybrids with short configurations have been intensively studied, less work has been done on hybrids with very long configurations. In this study, we investigated laboratory-reared wild mice from two chromosomally very different races in Switzerland found in close proximity. Hybrids between these races form a meiotic chain of fifteen chromosomes. We performed a detailed analysis of male and female hybrid fertility, including three generations of female backcrosses to one of the parental races. We also tested for possible divergence of mate preference in females.
While all male F1 hybrids were sterile with sperm counts of zero, 48% of female F1 hybrids produced offspring. Their litter sizes ranged from one to three which is significantly lower than the litter size of parental race females. When hybrid females were backcrossed to a parental race, half of the offspring resembled the parental race in karyotype and fertility, while the other half resembled the F1 hybrids. In the preference test, females of both races indicated a lack of a preference for males of their own karyotype.
Although the fertility of the F1 hybrids was extremely low because of the complexity of the chromosomal differences between the races, reproductive isolation was not complete. As we did not find assortative female preferences, we expect that contact between these races would lead to the production of hybrids and that gene flow would occur eventually, as fertility can be restored fully after one backcross generation.
- Centric fusion
- Hybrid fertility
- Hybrid dysfunction
- Mate preference
- Mus musculus domesticus
- Robertsonian fusion
Speciation is a central topic in evolutionary biology , with a need for detailed studies of incipient reproductive isolation of major genetic forms within species through an analysis of hybridisation either in the laboratory or in nature, i.e. where the races make contact at hybrid zones . One characteristic that can define major genetic forms within species is the presence of chromosomal rearrangements; such forms may be termed chromosomal races . Chromosomal rearrangements have the potential to be potent agents promoting reproductive isolation. Mechanical problems during meiosis in hybrids between chromosomal races may lead to subfertility or sterility (hybrid dysfunction) [4, 5]. These include incorrect pairing of parental chromosomes, malsegregation of chromosomes, and errors during crossing-over leading to deletion or duplication of chromosomal regions. In addition, chromosomal rearrangements can also suppress recombination and protect larger parts of the genome from introgression despite hybridisation, facilitating the accumulation of species-specific gene variants involved in Dobzhansky-Muller incompatibilities in these regions [6, 7]. Such incompatibilities may also be related to mate choice.
Chromosomal rearrangements between races and species of mammals include inversions, translocations and fusions/fissions. The western house mouse (Mus musculus domesticus) is an excellent model for the study of a very common rearrangement in mammalian karyotype evolution, the Robertsonian (Rb) fusion (= centric fusions): the joining of a pair of acrocentric chromosomes at their centromeres to form a metacentric . While the ancestral karyotype of the western house mouse consists of 2n = 40 acrocentrics, Rb fusions have led to metacentric races—over 100 have been described—with reduced diploid numbers down to 2n = 22 [9, 10]. Hybrids between these races have been shown to suffer a decrease in fitness linked to the complexity of their chromosomal differences . Similar observations have been made for hybrids between chromosomal races in other mammalian species [3, 11], although the house mouse is exceptional for the ease of laboratory studies and availability of genomic and other resources .
Simple heterozygotes with few trivalents (those with one to three have been well studied) show near-normal fertility, while those with a higher number of trivalents (up to nine) are more severely affected and show decreasing fertility with increasing number of trivalents [13, 14]. In contrast, complex heterozygotes usually suffer a more substantial decrease in fertility, with chain meiotic configurations being more detrimental than rings [15, 16]. Although the reduction in fertility is strongly linked to the complexity of the meiotic configurations, there also seems to be an effect of the genetic background [13, 17, 18]. Also, female heterozygotes are generally less severely affected than males [10, 15]. The most detailed studies of fertility of hybrids between chromosomal races, with substantial quantitative data, relate to simple heterozygotes and complex heterozygotes for short chain configurations. There are data for both males and females, but substantially more on males [13, 14, 17, 19–24].
In addition to the effect of chromosomal differences, geographic separation itself could lead to divergence of behaviour, which could act as a premating barrier if the races were to come into contact. Such premating divergence has been described between the western house mouse and its sister subspecies, the eastern house mouse Mus musculus musculus (e.g. [25, 26]). Therefore, we tested for female preference when given a choice between males of the two races.
Mice were kept either singly in Makrolon Type II cages or in groups in Makrolon Type III cages (Indulab). Groups consisted of same-sex siblings or of a breeding pair. Cages contained bedding, cardboard housing and paper towels as nesting material. Food and water was available ad libitum. Animals in the fertility experiment were kept under a light:dark cycle of 14:10 with lights on at 05.30 CET. Animals in the mate preference test were kept under a reversed cycle with lights on at 17.30 CET.
Details of animal numbers in all experimental crosses (see Fig. 4)
Number of offspring born
Number of offspring weaned
Number of crosses
Duration (mean ± SD) [days]
Sex unknown (died as pups)
2n = 23
2n = 24
2n = 23
2n = 24
137.7 ± 63.0
84.1 ± 43.2
62.8 ± 33.9
81.0 ± 52.3
Mitotic chromosome spreads were prepared according to Ford  and stained with Giemsa. For each individual, at least twenty clear and complete metaphases were counted. According to our expectations outlined in the Introduction (Fig. 2), all F1 mice were expected to have 2n = 23 chromosomes. We verified this by counting chromosomes of seven randomly chosen F1. After backcrossing to a male of the parental CHHN race with 2n = 24, we expected offspring of either 2n = 23 (hybrid karyotype) or 2n = 24 (parental CHHN karyotype). Thus, we made chromosome counts for offspring of all female 2n = 23 hybrid mice (this included offspring from BC1, BC2 and BC3 crosses). Chromosomes from offspring from 2n = 24 hybrid females (this included offspring from BC2 and BC3 crosses) were not counted.
Offspring were classified into three categories: (1) F1 hybrids with 2n = 23, (2) BC.23 hybrids with 2n = 23, resulting from backcrosses to CHHN, and (3) BC.24 hybrids with 2n = 24 also resulting from backcrosses to CHHN.
Fertility of males
Male offspring were sacrificed at an age of nine weeks (mean ± SD, 65 ± 3 d). Twenty-five male F1 hybrids were analysed. As controls, 12 male CHBU and 17 male CHHN of similar age were used (62 ± 3 d, 64 ± 5 d, respectively). The right cauda epididymis was processed as described in Hauffe & Searle . Spermatozoa were counted in both chambers of a Neubauer Improved haemocytometer. Sperm estimates were calculated by dividing the number of sperm by the volume of the haemocytometer squares counted (ten squares of 0.04 mm2 with 0.1 mm depth or, if no sperm was visible in that area, the whole 9 mm2) and then by multiplying with the total solution used to dilute the epididymis (2 ml). The results from both chambers were averaged for each male. The resulting value estimates the total number of sperm in one cauda epididymis. Other data collected from males were as follows: body mass after euthanasia, epididymis mass (mean of separate measurements of right and left complete epididymides), testis mass (mean of separate measurements of right and left testes), mass of seminal vesicle and coagulating gland (as these organs could not be reliably separated, they were weighed together; half the mass of combined left and right dissected as one entity) and preputial gland mass (half the mass of combined left and right dissected as one entity). Male offspring of backcrosses were processed in the same fashion (N = 21) and included male offspring from fully fertile BC2 and BC3 females (two per female). To increase sample size for these comparisons, we set up additional crosses in exactly the same way as the P crosses to provide 35 additional males (mean age 60 ± 3 d; 17 F1, 12 CHBU, 6 CHHN).
We applied linear mixed-effects models (LMM) with parent pair as a random effect in order to take into account that siblings were included in the analysis. Independent variables were category of male (CHBU, CHHN, F1, BC.23, BC.24) and body mass. We used the lme4, lsmeans and lmerTest packages in R 3.3.0 [30–33]. Denominator degrees of freedom were approximated using the Satterthwaite method. We tested the assumption of normality for all models in this study with a Normal Q-Q plot of the residuals. However, the assumption of normality was not well satisfied for sperm number. Thus we first applied a Fisher’s exact test to analyse the difference in prevalence of males with and without sperm depending on whether a meiotic chain of fifteen was expected or not (F1 and BC.23 vs CHBU, CHHN and BC.24). Then we applied the LMM described above on the male categories with sperm (CHBU, CHHN and BC.24) after performing a common logarithmic transformation on sperm number.
In order to demonstrate the presence of a meiotic chain configuration of fifteen chromosomes in F1 hybrids, we made diakinesis preparations from the testes of two male F1 hybrids according to Bulatova et al. .
Fertility of females
Female fertility was estimated by whether or not pups were born, and by the number of offspring in the female’s first litter (31 F1, 12 BC). For a subset of these females (19 F1, 12 BC), the number of implantation scars in the uterus was counted post mortem from fresh tissue [35, 36]. In order to attribute any decrease in fertility to the females rather than to the males, we performed sperm counts on the latter. As estimates for number of offspring in females of the parental races, we used data from the same breeding system of our laboratory that had furnished P mice and CHHN backcross males for this experiment. From all first litters born to females from within-race breeding pairs over the period 2013–2016, we randomly selected 12 litters from CHBUxCHBU crosses, and 12 litters from CHHNxCHHN crosses. We used a one-way ANOVA to compare litter sizes between experimental females and controls. Additionally, we performed a LMM on the data of the experimental females with litter size as the dependent variable, category of female and body mass as independent variables, and parent pair as a random effect to correct for the presence of full-siblings. The same R packages were used as for the analysis of male fertility. Plots were created using ggplot2 .
Female preference test
For the statistical analysis, the proportion of time P a female spent near the mesh of the CHHN male was calculated as (time at mesh of CHHN male)/(time at mesh of CHHN male + time at mesh of CHBU male). LMMs were performed following logit transformation of the response variable time proportion P. Transformations were performed using the boot package in R [45, 46]. Fixed effects were female race, difference in male body mass, difference in male age, and difference in time males spent near the mesh. All differences between males were calculated as (CHHN value) − (CHBU value). These differences were centred, and scaled to standardise variation. Random effects were ID of the male pair used and the chamber side the CHHN male was placed in (right or left, to correct for a potential preference of the female for a specific side).
The seven analysed F1 hybrids had a diploid chromosome number of 2n = 23 with 17 metacentrics and 6 acrocentrics. Offspring from F1 females had either 2n = 23 with 17 metacentrics and 6 acrocentrics (N = 4), or 2n = 24 with 16 metacentrics and 8 acrocentrics (N = 11). This was also the case for offspring from females with 2n = 23 from the BC1 and BC2 generation (offspring with 2n = 23: N = 4, offspring with 2n = 24: N = 3, Table 1).
Fertility of males
Mean and standard deviation for male fertility measurements for all groups
Body mass in g
25.0 ± 1.9
22.1 ± 3.0
23.7 ± 3.0
26.3 ± 1.3
23.6 ± 2.4
Number of sperm in cauda epididymis (103)
17,019 ± 5074
12,935 ± 3594
0 ± 0
0 ± 0
15,247 ± 5018
Testis mass in mg
93.22 ± 9.75
84.77 ± 12.11
34.56 ± 6.59
30.95 ± 3.33
90.91 ± 10.79
Epididymis mass in mg
28.24 ± 3.93
25.04 ± 4.40
16.27 ± 2.25
17.02 ± 0.61
28.43 ± 3.99
Mass of seminal vesicle with coagulating gland in mg
91.23 ± 22.87
65.60 ± 19.46
78.64 ± 15.65
99.10 ± 9.49
88.28 ± 25.19
Preputial gland mass in mg
47.39 ± 16.64
36.12 ± 21.45
54.22 ± 23.11
43.8 ± 10.35
48.84 ± 28.64
Results of ANOVA analyses of effect of male category and body mass on male fertility
Seminal vesicle and coagulating gland
Pairwise comparisons of reproductive parameters for different categories of males
Number of sperm in cauda epididymis (103)
Testis mass in mg
Epididymis mass in mg
Mass of seminal vesicle with coagulating gland in mg
Preputial gland mass in mg
Fertility of females
Pairwise comparisons of size of first litter for different categories of females using Dunnett’s method
Estimate of difference in litter size between contrasted races
The CHHN males used in the backcrosses had a mean ± SD number of sperm in the cauda epididymis of 23.1 ± 12.1 million, which is in the range of the sperm counts for CHHN control males in the male hybrid fertility analysis (Fig. 6).
Female preference test
Linear mixed model of logit transformed relative time proportion spent by female near CHHN male
Δ Male body mass
Δ Male age
Δ Male time spent at mesh
Studying hybridisation between major genetic forms within species is one approach to better understand the process of diversification. In this study, we investigated the effect of chromosomal rearrangements, specifically Robertsonian fusions, on the fertility of hybrids between two such genetic forms—chromosomal races—of house mice. F1 hybrids (2n = 23) between the races CHBU (2n = 22) and CHHN (2n = 24), which show substantial chromosomal differences, form a multivalent chain of fifteen chromosomes during meiosis. We report in a detailed analysis that male F1 hybrids are sterile while female F1’s have low fertility. Backcrossing of female F1 to males of the CHHN race resulted in the restoration of the CHHN karyotype and full fertility in half of the offspring. However, we consider hybrid fertility overall to remain relatively low as the occurrence of fertile offspring would be strongly limited by the very low F1 fertility, and the probability of a sterile backcross offspring. In the preference test, females did not show a preference for males of either race.
Spermatogenesis was disrupted in the male F1 hybrids, as they had sperm counts of zero with a lower mass of the testis and epididymis but normally sized seminal vesicle (measured with coagulating gland) and preputial gland. Low sperm counts linked to low testes mass have been previously described, e.g. in Flachs et al. . This tight relationship between sperm count and mass of the testis and epididymis is expected for physiological reasons, as sperm is located in these organs and should thus influence their mass.
Unlike the males, F1 female hybrids were partially fertile. Half of the F1 females produced litters upon backcrossing. However, it took them longer than for parental race females until their first litter was born and the number of offspring was significantly decreased. Most hybrid females had litter sizes of only one offspring instead of the usual six to seven observed in mice of the parental races. F1 females also had an excess of uterine scars that indicated that they had lost multiple foetuses. The cause is most likely aneuploidy. Aneuploid embryos and foetuses have been previously found in pregnant mice heterozygous for metacentrics . In addition, extremely high rates of nondisjunction, ranging up to 100%, have been described in female complex heterozygotes [15, 22]. Nondisjunction results in monosomic and trisomic zygotes after fertilisation. While monosomics die before implantation, trisomics usually survive past implantation and leave visible scars in the uterus [49, 50]. Thus, the scars in the F1 females could indicate the loss of trisomic foetuses.
The fertility results of these F1 hybrids concur with previous studies on complex heterozygotes with long chain configurations during meiosis [15, 16, 18, 51, 52]. In general, male-limited sterility with disrupted spermatogenesis has been observed. However, these studies are mostly qualitative, some without detailed information on sample sizes or the races that were crossed. In addition, the fertility of females was not always investigated. We aimed to contribute a detailed and complete study of complex heterozygote fertility. The most similar study to ours is that of Capanna et al. , in which fertility of F1 hybrids between the Poschiavo race (2n = 26) and the Cittaducale race (2n = 22) were studied. These complex heterozygotes possess a chain of seventeen and a chain of three chromosomes during meiosis. Preparation of spermatocytes from nine male hybrids and histological inspection of the testes of eight males indicated that the formation of mature sperm was absent. In contrast, 13 oocyte preparations of meiosis II could be collected from eight female hybrids. Of the ten female hybrids that were crossed to fertile males during four to five months, only two litters with one offspring each were obtained. Both of these offspring were sterile, although no information on karyotype was given. These results are similar to our findings, although female F1’s between the CHBU und CHHN races appear to have a higher fertility. This could be due to them having only one, slightly shorter, meiotic chain with fifteen chromosomes or to a more similar genetic background, as these races are geographically more closely located than the Poschiavo and Cittaducale races.
Thus in Capanna et al.  and the current study, gametogenesis in complex heterozygotes with very long chain configurations was affected differently in males and females. This accords with Haldane’s Rule , and matches findings in mice that mutations affecting meiotic chromosome alignment and segregation generally have stronger effects in sperm than in oocytes, with cessation of spermatogenesis and continued oogenesis . Garagna et al.  studied oogenesis directly and found that in heterozygous metacentric mice, egg follicles that successfully pass the first stages of oogenesis also finish their development. In addition, they described a reduction in follicle number for complex heterozygote females with long meiotic chains, indicating a shorter reproductive lifespan. We thus expect CHBUxCHHN F1 females not only to suffer from reduced litters and an increased number of aneuploid offspring due to nondisjunction, but to also suffer a decrease in reproductive lifespan due to a smaller supply of follicles.
We expected that backcrossing female F1 (2n = 23) to CHHN males (2n = 24) would lead to two types of offspring (Fig. 2): those with a hybrid karyotype (2n = 23) and those with the CHHN karyotype (2n = 24). This pattern was corroborated in our findings. In addition, the fertility analyses showed that when the CHHN karyotype was restored in the offspring, their fertility was normal and equal to that of mice of the parental races. In contrast, offspring with the F1 hybrid karyotype displayed the fertility of the F1 hybrids with sterility in males and low fertility in females. Under the assumption of no recombination (a very simplified scenario), we would expect backcross offspring with 2n = 24 chromosomes to not only regain the parental karyotype, but also the genetic material from the chain chromosomes of that race, while offspring with 2n = 23 would be genetically heterozygous for all chain chromosomes (Fig. 2). However, there is strong support that recombination is obligate in mice and other mammals  and studies on simple heterozygotes between mouse chromosomal races have shown that a minimum of one recombination event is maintained [56–58]. While complex heterozygotes with long chains have not yet been studied, it would seem probable that recombination rates remain close to the seemingly obligate one recombination event per chromosome arm. Thus, under the assumption of recombination, offspring from backcrosses should be genetic hybrids, even if they have the karyotype of a parental race. As no intermediate fertility values were observed, karyotype and fertility restoration seem to be directly related, suggesting that the decrease in fertility in hybrids between CHBU and CHHN is entirely due to chromosomal heterozygosity instead of genic incompatibilities or other genic effects. Even closely related individuals such as full siblings showed opposite fertility patterns if their karyotypes differed. These results differ from findings of studies in which the fertility of hybrids between mouse chromosomal races varied and indicated a possible involvement of a genic effect [13, 17, 22]. Nevertheless, as chromosomal races in the house mouse all belong to the same subspecies, the accumulation of Dobzhansky-Muller incompatibilities seems unlikely.
We did not find a preference for males of the same chromosomal race in our behavioural test, in which differences in the duration of proximity of the female to each male was used as a proxy for mate choice, a common experimental design , and in which differences in male behaviour, age and body mass were accounted for in the analysis. These results suggest that females would not discriminate between males of compatible versus incompatible karyotype in their mate choice. In a system of chromosomal races on Madeira, assortative preferences were also absent, although the races did show a divergence of their preference . Furthermore, behavioural differences between neighbouring metacentric races have been previously described [61–63]. In our study, we found a trend for an effect of male behaviour and a significant effect of age on the females’ behaviour. Thus, females may have been responding to other cues, e.g. of male quality or interest. In addition, we cannot exclude that laboratory rearing had an effect on the expression of female preferences or male traits.
As there does not seem to be assortative mating preferences between the CHBU and CHHN races, we expect contact to lead to the formation of F1 hybrids and, as female F1’s are not sterile, to allow gene flow between the races, potentially opposing the evolution of assortative mating. As fertility is further restored in part of the backcross offspring, we expect gene flow to be higher than expected when only considering F1 fertility.
This study presents a detailed report on fertility of laboratory-reared hybrids between two chromosomal races of house mice with a high complexity of chromosomal differences. Despite the long meiotic multivalent of fifteen chromosomes in F1 hybrids and sterility of male F1’s, female F1’s remained fertile, although to a low degree. Backcrosses of these females to males of one of the parental races resulted for part of the offspring in restoration of the karyotype to that of the parental race and full fertility, indicating that the decrease in fertility of hybrids is likely entirely due to karyotype. The remaining offspring had the karyotype and low fertility of F1 hybrids, with males being sterile and females having low fertility. A preference test on females of the parental races indicated a lack of preference for chromosomally compatible males. Thus, these races are expected to hybridise in the event of contact. While the chromosomal differences have the potential to promote reproductive isolation between the races through the extremely low fertility of F1 hybrids, the marginal fertility of female F1’s combined with the restoration of fertility in part of the offspring from backcrosses could lead to more gene flow than expected based solely on the length of the chain configuration in hybrids.
We warmly thank Barbara König for her support throughout and landowners who allowed us to trap mice at their properties and the many trapping volunteers.
Funding was provided by the University Research Priority Program “Evolution in Action” of the University of Zurich, the Claraz-Stiftung, the Promotor-Stiftung, and the University of Zurich.
AL and SG designed the study. EW performed the preference test. EW and SG trapped the mice. SG performed the crosses, fertility analyses and statistics.
SG, JS and AL wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Experiments were performed in accordance with the Swiss law and with the ethics approval of the Veterinary Office Kanton Zürich, Switzerland (licence no. 64/2014).
Consent for publication
The authors declare that they have no competing interests.
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