A model of the evolutionary accumulation of highly repeated DNA (HRDNA) is proposed. The accumulation of HRDNA sequences, which are organized largely in tandem arrays and whose functional significance is obscure, is explained here as a consequence of the action of the forces of amplification (promoting increase in copy numbers) and unequal crossing over, random drift and natural selection (controlling copy numbers). This model provides a general framework (i) to study the chromosomal location of satellite DNAs present in the genomes of all higher eukaryotes, and (ii) to explain the significant variation in the amounts of satellites which is frequently found among closely related species, but only rarely within a species. A review of the relevant data is included and open questions are identified.

A model of the balance between mutations and stabilizing selection affecting a quantitative character is developed and analysed. This model is essentially a discretized version of the continuum-of-alleles models analysed previously by Kimura, Lande, Turelli and others, and is formally similar to the stepwise mutation models used to interpret electrophoretic data. The complete model cannot be solved even for a haploid species, but there are useful approximations for most parameter values of interest. The ‘house-of-cards’ approximation can be used when selection is strong relative to mutation, and a normal approximation can be used when selection is relatively weak. For intermediate levels of selection a new ‘five-allele’ approximation provides accurate results over a wide range of parameter values. The house-of-cards and five-allele approximations applied to recessive alleles in a diploid population show that, for a given mutation rate, a somewhat larger genetic variance is maintained at equilibrium than in a comparable model of additive alleles. Under directional selection, the increase in genetic variance is largest for alleles of large effect and is much smaller for alleles of intermediate or small effect. At an equilibrium under stabilizing selection, homozygotes would tend to have a higher average fitness than heterozygotes when each mutation has a relatively large effect (the house-of-cards approximation), with the reverse if each mutation has a small effect (the normal approximation).

Irradiation has been employed successfully to increase the reverse mutation rate at the agouti and dilute loci in the mouse. The dilute allele has previously been shown to be due to the insertion of an ecotropic-specific murine leukaemia virus in the vicinity of the dilute locus, and its instability to be due to the excision of the proviral sequence (Jenkins et al. 1981). Molecular analysis of the recovered radiation-induced revertant at the dilute locus indicated excision of all but approximately 500 bp of the proviral sequence. The proviral sequence remaining in the mouse genome hybridizes to a probe specific for the proviral long terminal repeat (LTR) sequence. Previous characterization of two spontaneous reverse dilute mutations indicated precise proviral excision of all but a single LTR, and suggests homologous recombination between the proviral LTR sequences as the mechanism of proviral excision (Hutchison, Copeland & Jenkins 1984). The present results indicate that radiation and increases the reverse mutation rate at the dilute locus acts by a similar mechanism, and suggest that mutagenic treatment may be employed to produce genetic variants of interest.

Five class II H-2 genes borne by t chromosomes were partially sequenced: borne by the tTuw10 chromosome of EDY589 (H-2w2); and borne by the tTuw8 chromosome of CR0437 (H-2w57), as well as and borne by the tTuw7 chromosome of CR0435 (H-2w37). These genes are representatives of the three major groups of alleles found associated with t chromosomes. The sequenced part consisted of almost the entire exon 2 and the entire exon 3 coding for the first and the second domain of the β polypeptide chains, respectively. The sequence was compared with the published sequences of Aβ and Eβ alleles borne, by non-t chromosomes. The comparison revealed that the t-associated alleles are no more similar to one another than they are to the corresponding genes present on non-t chromosomes in laboratory mice. This divergence in the nucleotide sequence among the class II genes is interpreted as evidence that the t complex is very old.

We have utilized isoelectrofocusing two-dimensional polyacrylamide gel electrophoresis (IEF-ID-PAGE) to determine the frequency of variant proteins detected in mouse testes, and to examine an inbred strain with spermatogenic abnormalities. The observed frequency of variants, 4·2 ± 1·0%, is comparable to results reported for liver. A variant for a protein, identified as tubulin by immunoblotting, was observed in an inbred strain (PL/J) which has defective spermatogenesis, but was also observed in another inbred strain without spermatogenic defects. The gene symbol Tbn is proposed for this β-tubulin locus.

The covariance of an ancestor and the average of its descendants in generation t(CPt) is formulated for a breeding system which is a mixture of selfing and outcrossing. This covariance is partitioned into least squares additive (σA. At) and non-additive (σD. Dt) components summed over individual loci, and the combined inbreeding effects of all loci (H′), such that CPt = σA. At + (s/2)t[σD. Do + H′]. For the mth locus the covariance mσA. At = 2(1 + F)Σipiα(0)iα(t)i, in which pi is the frequency of the ith allele whose additive effect (α(t)) depends on the generation for which it is defined. For distant descendants α(∞) is equal to half of the derivative of the population mean with respect to the frequency of the allele. The covariance CP∞ = σA. A∞ thus relates directly to permanent selection response measured in the equilibrium population, any additional responses observed in earlier generations being due to temporary disturbances in population genotypic structure. It is only for these distant descendants that the least squares additive component has any direct interpretation in terms of selection response. The definitions of α(0) and α(∞), lead to two distinct definitions of the average effect of an allele substitution for a model with two alleles (Fisher, 1941), and to a clarification of their significance for this breeding system.

In the mouse histidinaemia has a teratogenic effect. Animals subjected to high levels of histidine in utero may develop inner ear and behavioural abnormalities typical of the ‘shaker–waltzer’ syndrome. Selection procedures for abnormalities and relaxation of selection have resulted in two histidinaemic strains: the Cambridge strain in which abnormalities occur in over 80% of animals, and the Edinburgh strain in which the penetrance of abnormal behaviour has declined to about 1%. Breeding experiments suggest that the differences are largely due to differences in the genetic backgrounds which modify foetal susceptibilities to the teratogenic effects of high histidine levels. High susceptibility appears to be dominant over low susceptibility in the present strains. There appears to be no interaction of maternal histidinaemia with the dreher mutation which is considered to induce inner ear malformation as a result of an early neural tube abnormality.

Kimura used the heterozygosity and the number of low-frequency alleles to estimate that about 14% of mutations are selectively neutral. The method is shown to be subject to biases and to disruption due to bottleneck effects. Let deleterious alleles have selective disadvantage, s, compared with neutral alleles and let Ne denote the effective diploid population size. The estimator, , of the proportion of neutral alleles is positively biased if (roughly) 4NeS < 25 or if 4Nes > 200. In the former case, one cannot adequately detect the different influences of deleterious and neutral alleles, whereas in the latter case, deleterious alleles will rarely appear in the sample. These difficulties cause the biases in , and are likely to cause similar biases for any estimation method based solely on allele frequencies. There is substantial sampling variability in in cases of practical interest, when data from 11 loci, or even as many as 31 loci, are pooled. If there has been a recent contraction in population size, will be positively biased, often yielding values greater than 1 or even being infinite. But after a recent expansion in population size, the heterozygosity will not have made as quick an increase and will be negatively biased. Population expansion alone can produce values close to those observed by Kimura, even if all alleles are neutral. In an appendix, a new method for simulating samples of neutral and deleterious genes is described.

Mice are the most widely used experimental mammals, and many inbred strains are available. However, except for the relatively recent strains derived from known wild populations, the relationships between wild and laboratory mice are not well understood. Based on the Y-chromosomal restriction fragmentlength polymorphism, seventeen inbred strains were classified into two groups: strains with the Mus musculus musculus type Y chromosome and those with the M. m. domesticus type Y chromosome. We extended the survey to an additional twenty-two inbred strains. The M. m. musculus type Y chromosome was found in AEJ/GnLe, AAU/SsJ, BDP/J, BXSB/MpJ, DA/HuSn, HTG/GoSfSn, I/LnJ, LP/J, NZW/LacJ, RIIIS/J, SB/Le, SEA/GnJ, SF/CamEi, SK/CamEi, SM/J, WB/ReJ, WC/ReJ and YBR/Ei, while the M. m. domesticus type Y chromosome was present in BUB/BnJ, MA/MyJ, PL/J and ST/bJ.

The influence of mutations in chromosome 17 upon the segregation of the metacentric and acrocentric homologues in the progeny of female mice heterozygous for Robertsonian translocations Rb(8.17)11em and Rb(16.17)7Bnr was studied. Genetic analysis indicated that the portion of non-Rb (normal karyotype) progeny from mothers heterozygous for mutations tf, qk, t12 was weakly different from the 50% Mendelian expected level (55–57%). Introduction of mutations T, FuKi, Fu, t6 into the female genotype caused a stronger segregation distortion and an increase in the portion of progeny with normal karyotype (63–67%). From the data on embryonic mortality and cytogenetic observations it is concluded that a distortion of equal transmission arises before M II of meiosis. Consequently, the preferential distribution of the metacentric chromosome to the polar body during the first meiotic division is relevant to the observed segregation distortion.

An animal with low erythrocyte triose phosphate isomerase (TPI) activity was found amongst mice trapped on a farm in Leicestershire. The low TPI activity was caused by the segregation of a single co-dominant gene which also affected the Km for glyceraldehyde-3-phosphate and heat stability of the enzyme. We designate the gene Tpi-1, the structural locus for TPI, with the a allele in the common inbred strains and the b allele derived from the wild-caught mouse. Tpi-1 was known to be on chromosome 6 by somatic cell techniques and, as shown in a preliminary report (Peters & Bulfield, 1984), we have confirmed and extended this finding using three chromosome-6 marker genes giving the order: Sig-28-Lc-11-Miwh-16-Tpi-1.

Twelve isogenic X chromosome lines from a single natural population of Drosophila melanogaster were tested for their potential to induce gonadal dysgenesis and singed-weak mutability in P-M hybrid dysgenesis. The correlation between sterility and mutability was significantly positive for Cross A, confirming the results reported by Engels (1984) and Kocur, Drier & Simmons (1986). In Cross A* cytotype tests, however, two of the lines gave strikingly different results when measured by the gonadal dysgenesis test as compared to the singed-weak test. Positive correlations between traits within a given line were generally not observed. The results suggest that the relationship between gonadal dysgenesis production and the mobilization of P elements in singed-weak mutability is more complicated than that proposed by Engels (1984). The two phenomena may be separable under certain conditions. Neither test can be taken as an adequate characterization of the hybrid dysgenesis ‘profile’ of a line of flies.

Genet. Res., Camb. (1987), 49, pp. 11–18

A latitudinal cline in P–M gonadal dysgenesis potential in Australian Drosophila melanogaster populations

Figures 1 and 2 have been interchanged with their legends. Thus the maps shown as Fig. 2 belong to the legend of Fing. 1, and should be labelled Fig. 1, and vice versa.

Genet. Res., Camb. (1986), 48, pp. 175–178

A chromosomal segment conserved since divergence of lineages leading to man and mouse: the gene order of aminoacylase-1, transferrin and beta-galactosidase on mouse chromosome 9

In the summary on page 175 and in the last paragraph on page 176, the second aminoacylase locus, Acy-2, was inadvertently described as requiring MgC12. The correct compound is MnC12.

An estimator is proposed for the parameter C = 4Nc. where N is the population size and c is the recombination rate. The estimator is appropriate for use with sequence or restriction site data from random samples from within populations. Properties of the estimator are investigated for an infinite-sites neutral model using Monte Carlo simulations. The median and mode of the distribution of the estimator are close to the true value for all parameter values examined, but large data sets are required to obtain reliable estimates.

Genet. Res., Camb. (1986), 47, pp. 83–91

Structural Genes for Phosphatases in Aspergillus nidulans

A labelling error caused nimD-4 to be substituted for nimQ-20. The nim locus shown in Fig. 3 (p. 88) is nimQ not nimD. The genotypes of strains given in the legend to Fig. 3 should read nimQ-20 in place of nimD-4.

Genet. Res., Camb. (1987), 50, pp. 17–21

Heterogeneity of human haptoglobin α chains detected by two-dimensional gel electrophoresis

The running title for this article should have been Human plasma haptoglobin α chain heterogeneity

Genet. Res., Camb. (1987), 50, pp. 63–68

Additive variance and average effect with partial selfing

(1) The second line of Table 1 should read