Lethal Haplotypes Research Articles

An additional type of male sterility and inherited urinary obstruction in mice with the t-haplotype th7.

The t-complex on mouse chromosome 17 results in transmission ratio distortion in males heterozygous for complete haplotypes, and sterility in those homozygous for semi-lethal or doubly heterozygous for complementing lethal haplotypes. This sterility is due to inability of spermatozoa to fertilize. The haplotype th7 is an unusual laboratory-derived haplotype, postulated to carry a small duplication of t chromatin. Males heterozygous for th7 show a new form of sterility, apparently due to failure to form copulation plugs during mating. This is accompanied by a strong propensity to acute urinary obstruction. It is suggested that both the failure to form copulation plugs and the urinary obstruction are due to some abnormality in function of the accessory sex glands, and are the result of incorrect dosage of a gene in the postulated duplication. The symbol Msu for male sterility and urinary obstruction is suggested for the locus concerned. Previously a recessive form of abnormal behaviour had also been attributed to this duplication.

The evolution of lethals in the t-haplotype system of the mouse.

The evolution of lethal haplotypes in the t-haplotype segregation distortion system of Mus is examined by mathematical and computer models. The models assume that there is reproductive compensation for the loss of lethal embryos, such that the net reproductive success of a females is not reduced in proportion to the frequency of lethal offspring which she produces. The initial population consists of a mixture of wild-type and homozygous male-sterile t-haplotypes. The failure of sterile males to reproduce may cause a higher fitness cost to mothers heterozygous for t-haplotypes than does elimination of a recessive lethal. Under certain conditions, a recessive lethal will spread and come to a polymorphic equilibrium. Wild-type, lethal and non-lethal haplotypes are all present at this equilibrium. If a second lethal mutation arises on a non-lethal t-haplotype in such an equilibrium population, it will increase in frequency and eventually displace the non-lethal t-haplotypes. A third lethal t-haplotype introduced at a low frequency into an equilibrium with two lethals can sometimes be selected for, although this is less likely if compensation is strong. The theoretical predictions are compared with data on natural populations.

Female Preference and Variability Among t-Haplotypes in Wild House Mice

Many wild house mice are heterozygous (+/t) for a t-haplotype at the t-complex. Most t-haplotypes carry recessive lethal factors causing embryonic mortality of homozygotes Many different t-haplotypes coexist in mouse populations. Fetal death occurs when mice are homozygous for lethal haplotypes from the same complementation group. If the mouse carries two t-haplotypes from different complementation groups, it survives, but all such males are sterile. We gave +/tw12 and +/tw32 females a choice between +/tw12 and +/tw32 males Females preferred the male carrying a t-haplotype different from their own. This disassortative preference was stronger for +/tw12 than for +/tw32 females. We paired +/tw12 and +/tw32 females to males of each genotype and measured the number of fertile progeny produced. Fitness of +/tw32 females was slightly higher when they were mated to males of the opposite genotype; fitness of +/tw12 females was much higher when they were mated to +/tw32 than when mated to +/tw12 males. Hence, female preferences for genetically based male cues may track fitness consequences of mating. Female preference combined with a fitness advantage for disassortative mating among haplotypes may maintain the high degree of genetic variability in this region.

THE ROLE OF DEME SIZE, REPRODUCTIVE PATTERNS, AND DISPERSAL IN THE DYNAMICS OF t-LETHAL HAPLOTYPES.

The t-lethal haplotypes (t) found in house mouse (Mus musculus) populations are recessive lethals favored by gametic selection whereby male heterozygotes exhibit a non-Mendelian transmission ratio of about 95% t. The expected equilibrium frequency is 0.385; however, empirical values are lower, averaging close to 0.13. We examined the hypothesis that interdemic selection is the cause of the low empirical values by using a deme-structured simulation model that included overlapping generations, a realistic breeding system, differential deme productivity, and a large total population. We found that under some conditions interdemic selection could lower t frequency below 0.13 in the face of immigration rates up to 5%. Low frequencies were correlated with effective deme size (ne ), regardless of whether ne was changed through changing deme size (n) or through changing the proportion of breeding adults. Earlier workers showed how the first two phases of interdemic selection (random genetic differentiation and mass selection) interacted to reduce the haplotype frequency, but here we show the importance of the third phase (differential productivity of demes) once demes are linked by dispersal. The effect of this phase is not due to the (negative) covariation between deme productivity and haplotype frequency, but occurs when differential deme productivity generates a difference in t frequency between the population of juveniles recruited into their natal deme and the population of juvenile dispersers. This difference was maximized when the average productivity of demes was low, either because few adult females bred at any one time and/or because fecundity was low. Contrary to an earlier prediction, male-biased dispersal also reduced haplotype frequency, and this probably stems from the relative excess of wild-type genotypes among dispersers compared to the deme residents. Another unexpected finding was that the randomly generated excess of heterozygotes (FIS < 0) found in small demes favored t haplotypes; however, the effect was only seen when the more powerful influence of the third phase of interdemic selection was removed. Simulations of neutral polymorphisms showed that a deme structure giving FST ≤ 0.6 is inconsistent with a haplotype frequency below 0.13. Based on current empirical estimates of FST (about 0.2), we concluded that immigration rates in the field are too high for interdemic selection alone to cause the observed deficit of lethal haplotypes. One factor that could combine with population structure effects is the observation that the transmission ratio is lowered to around 0.6 in litters produced from postpartum estrus (PPE). Incorporating this factor, we showed that interdemic selection could be effective in lowering the frequency of t below 0.13 when FST was above 0.43 even when migration rates were up to 10%. These results suggest that if empirical haplotype and FST estimates are accurate, then additional factors such as a lowered fitness of heterozygotes may be involved.

Genetic organization of the mouse t complex

The mouse t complex (also known as the T locus or T/t complex) is a large region of chromosome 17 that has intrigued geneticists for more than 50 years with its striking and unorthodox features. These include suppression of recombination, disturbances of embryonic development and alterations of sperm differentiation and function. Much of our knowledge concerning the properties of this genetic complex is based on the early work performed by S. Gluecksohn Waelsch and L. C. Dunn with mutant forms of the t complex called t haplotypes (previously known as t alleles or t mutations). Many t haplotypes are characterized by lethal actions at particular stages during early embryogenesis. Lethal t haplotypes can be placed into a number of groups where members of each group do not complement each other. Complementation between t haplotypes of different groups is not complete, and prenatal death occurs in many, but not all, doubly heterozygous (V/t”) embryos. Furthermore, all males doubly heterozygous for two lethal haplotypes are completely sterile. Other genes defined separately from t haplotypes but mapping within the t complex include Brachyury (T), Kinky (Fuk’) and Knobbly (Fukb), which are recessive embryonic lethals; Hybrid sterility-l (Hst-7) and Quaking (qk), which cause male-specific sterility; Hye, which affects the level of male-specific H-Y antigen expression; and Gtl, which determines acceptance or rejection specifically of embryonal carcinoma cell grafts. All observations to date imply a crucial role for the t complex in mechanisms of development and differentiation. At the present time, however, the molecular events responsible for these t complex effects remain elusive. This review will therefore focus on recent advances in our understanding of the structure, rather than the function, of this region. All known t haplotypes originated from wild populations, and almost all wild mouse populations analyzed from around the world have been found to be polymorphic for lethal or semi-lethal t haplotypes. Maintenance of a deleterious gene in a wild population is unexpected, but can be accounted for in this case by a further property of t haplotypes called transmission-ratio distortion (also known as segregation distortion). A wild heterozygous (+/t) male can transmit his t haplotype to more than 95% of his offspring, and it appears that the advantage of the t haplotype at fertilization can overcome the disadvantage of a certain frequency of homozygous lethality in the population as a whole. Genetic systems that involve the maintenance of deleterious gene complexes in wild populations by transmission-ratio distortion have been identified in other well studied species, and include the SD complex of Drosophila melanogaster, and the Spore Killer (SK) complex in Neurospora (Turner and Minireviews

Recombination suppression of mouse t-haplotypes due to chromatin mismatching.

We show here that recombination occurs at the normal rate in compound female mice containing two different complementing lethal haplotypes (th17/tw12) where there is a long stretch of homologous t-mutant chromatin. Thus the recombination suppression of a complete t-haplotype cannot be due to an intrinsic factor(s) which suppresses along the length of its own chromosome but is due to 'mismatching' of wild-type and mutant chromatin. Naturally occurring t-haplotypes of mouse chromosome 17 have several interesting genetic properties. First, they are always transmitted from males in much higher proportions than mendelian expectation; presumably this accounts for the maintenance of lethal and semilethal t-haplotypes at polymorphic levels in populations of wild mice. t-Haplotypes also show recombination suppression. The conventional map distance between genetic markers T and tf is 7-12 cM, whereas in (t/+) heterozygotes for naturally occurring t-haplotypes, recombination is suppressed and T and tf seem to be separated by only 0.1-0.5 cM (ref. 1). The region of recombination suppression extends to and includes the major histocompatibility complex (H-2). Thus t and H-2 effectively travel as a single unit-- a 'super gene'. Although recombination suppression is known to be accompanied by failure of chiasmata formation, the mechanism underlying the suppression has remained an enigma. Lyon suggested a disorder of t-heterochromatin and more recently a change in 'intercalary' middle repetitive DNA. She proposed that either t-chromatin is intrinsically incapable of participating in crossing-over, or chiasma formation is prevented because of mismatching and mispairing of normal and abnormal chromatin. We have measured recombinant between two chromosomes which carried extensive overlapping segments of t-chromatin. We report here that in this configuration, recombination occurs at a normal rate, and thus we conclude that cross-over suppression is due to mismatching.

Relationship of F9 antigen and genes of theT/t complex

Serological studies relating F9 antigen of embryonal carcinoma cells to[Formula: see text] at the murineT/t complex have been extended and confirm that only the lethal haplotype t(12)- and none of the other five lethal haplotypes-affects the quantitative expression of F9 antigen on sperm. Cytotoxicity tests on preimplantation embryos show that t(12) homozygotes are less susceptible to antiF9 serum than t(w5) homozygotes, and that using specific antimutant haplotype antisera prepared against sperm, t(12) antigen is detectable on morulae, whereas t(w5) antigen is not.

Success in Fighting of Two Varieties of Mice

Previous articleNext article No AccessLetters to the EditorsSuccess in Fighting of Two Varieties of MiceP. G. Martin and H. G. AndrewarthaP. G. Martin Search for more articles by this author and H. G. Andrewartha Search for more articles by this author PDFPDF PLUS Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by The American Naturalist Volume 96, Number 891Nov. - Dec., 1962 Published for The American Society of Naturalists Article DOIhttps://doi.org/10.1086/282246 Views: 5Total views on this site Citations: 9Citations are reported from Crossref PDF download Crossref reports the following articles citing this article:Leonard Nunney, Ann Eileen Miller Baker THE ROLE OF DEME SIZE, REPRODUCTIVE PATTERNS, AND DISPERSAL IN THE DYNAMICS OF t -LETHAL HAPLOTYPES, Evolution 47, no.55 (May 2017): 1342–1359.https://doi.org/10.1111/j.1558-5646.1993.tb02159.xSarah Lenington The t Complex: A Story of Genes, Behavior, and Populations, (Jan 1991): 51–86.https://doi.org/10.1016/S0065-3454(08)60319-8SARAH LENINGTON Reproductive Behavior as a Phenotypic Correlate of T-Locus Genotype in Wild House Mice: Implications for Evolutionary Models, Annals of the New York Academy of Sciences 474, no.1 Reproduction1 Reproduction (Dec 1986): 141–147.https://doi.org/10.1111/j.1749-6632.1986.tb28006.xPatricia Franks, Sarah Lenington Dominance and reproductive behavior of wild house mice in a seminatural environment correlated with T-locus genotype, Behavioral Ecology and Sociobiology 18, no.66 (May 1986): 395–404.https://doi.org/10.1007/BF00300513Ann Eileen Miller Baker GENE FLOW IN HOUSE MICE: INTRODUCTION OF A NEW ALLELE INTO FREE‐LIVING POPULATIONS, Evolution 35, no.22 (May 2017): 243–258.https://doi.org/10.1111/j.1558-5646.1981.tb04884.x Louis Levine , Robert F. Rockwell , and Joseph Grossfield Sexual Selection in Mice. V. Reproductive Competition between +/+ and +/tw5 Males, The American Naturalist 116, no.11 (Oct 2015): 150–156.https://doi.org/10.1086/283619J. G. Oakeshott Social dominance, aggressiveness and mating success among male house mice (Mus musculus), Oecologia 15, no.22 (Jan 1974): 143–158.https://doi.org/10.1007/BF00345742J. H. F. van Abeelen Behavioural profiles of neurological mutant mice, Genetica 37, no.11 (Dec 1966): 149–158.https://doi.org/10.1007/BF01547126Joan Staats Behaviour studies on inbred mice: A selected bibliography, II, Animal Behaviour 11, no.44 (Oct 1963): 484–490.https://doi.org/10.1016/0003-3472(63)90266-5