Delineation of the t complex on mouse chromosome 17 by in situ hybridization.
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Animals↗
Biomedical subjects
L M Silver
Publications and source records attributed to L M Silver.
Distortion of transmission ratio by a candidate t complex responder locus transgene.
The mouse t complex responder locus (Tcr) is centrally involved in the phenomenon of male-specific transmission ratio distortion (TRD) through its action in haploid germ cells. Previously, we identified a candidate gene, Tcp-10b, whose t allele generates alternatively spliced transcripts. The full-length Tcp-10bt transcript is present in pre- and postmeiotic germ cells and encodes a product that is virtually identical with that encoded by the wild-type allele. The alternatively spliced t-specific transcript is observed in post-meiotic haploid spermatids and would encode an altered polypeptide that could convey the Tcrt phenotype. To assess their function, we have introduced constructs representing each Tcp-10bt transcript into transgenic mice. Breeding experiments demonstrate that these two constructs alter the transmission ratios of t haplotypes from male mice, but in opposite directions. The results provide support for the hypothesis that Tcp-10bt is a component of the Tcr locus.
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Localization of the Mas proto-oncogene to a densely marked region of mouse chromosome 17 associated with genomic imprinting.
The mouse homolog of the human proto-oncogene MAS was mapped by two interspecific backcrosses to the proximal portion of MMU17. Higher resolution mapping was accomplished through the analysis of genotypes duplicated or deleted for a megabase-size subregion within MMU17. The results demonstrate a map position for Mas in the close vicinity of Igf2r, which encodes another membrane receptor known to undergo genomic imprinting. The data provide further evidence for the clustering of genes in a 1-Mb region of chromosome 17, with the absence of any identified genes in a nearby region likely to be six times larger.
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Genetic mapping of three human homologues of murine t-complex genes localizes TCP10 to 6q27, 15 cM distal to TCP1 and PLG.
Human homologues of mouse t-complex genes have been cloned and localized physically to chromosome 6p or 6q. TCP1, TCP10, and PLG are human homologues of genes located in the proximal portion of the t-complex on mouse chromosome 17. We present here results of genetic mapping of these human t-complex homologues previously localized to 6q25-q27, 6q21-q27, and 6q26-q27, respectively, by physical techniques. TCP1 and PLG do not recombine with each other and are separated from TCP10 by about 15 cM, while the corresponding mouse genes are no more than 4 cM apart. Genetic mapping with markers well localized cytogenetically places TCP1 and PLG proximal to TCP10 and localizes the latter to the cytogenetic band 6q27. It is likely that the organization of human t-complex homologues on 6q is similar to that of t haplotypes rather than that of wildtype murine chromosome 17.
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Concerted evolution of the mouse Tcp-10 gene family: implications for the functional basis of t haplotype transmission ratio distortion.
The mouse Tcr locus is defined by its central role in the transmission ratio distortion phenotype characteristic of t haplotypes. A molecular candidate for Tcr has been identified in the form of a gene--Tcp-10b--expressed during spermatogenesis. Tcp-10b is one member of a multigene family present in two to four copies on different homologs of chromosome 17. The coding regions of the Tcp-10 genes present within two inbred strains were compared with those of the tw5 haplotype. The various gene family members are highly conserved relative to each other with a minimum nucleotide identity of 98.6% in all pairwise comparisons. Maximal parsimony analysis indicates that the Tcp-10 gene family has evolved in a concerted manner with the obliteration of nearly all individual gene-specific characteristics. As a consequence, the candidate for the full-length mutant Tcr gene product is distinguished by only a single, highly conservative, amino acid change. The data are consistent with the hypothesis that the effector of mutant Tcr activity is a second, alternatively spliced product that is expressed in a haploid- and allele-specific manner.
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RFLPs detected with the human TCP10 gene, a homologue of a mouse t-complex gene.
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Animals↗
Allele- and haploid-specific product generated by alternative splicing from a mouse t complex responder locus candidate.
Mouse t haplotypes represent a variant form of chromosome 17 that has evolved the ability to propagate through natural populations by the phenomenon of 'transmission ratio distortion' (TRD), in which heterozygous +/t males transmit their t-carrying chromosome to 95% or more of their offspring. Although multiple t-associated loci have a role in expression of this phenotype, only one--the t complex responder (Tcr) locus--is responsible for determining which of the two homologues of chromosome 17 will be transmitted at a high ratio. A candidate gene (Tcp-10b) for Tcr that is expressed in both meiotic and post-meiotic male germ cells has been cloned. But for this candidate gene to function as the haploid effector of TRD, the t-allele of this gene (Tcp-10bt) must express a unique product in a haploid-specific manner. Here we show that a change in the splicing pattern of Tcp-10bt transcripts occurs during sperm differentiation. This change results in a unique allele-specific and haploid-specific transcript which could encode a variant polypeptide that would fulfil the conditions required of the Tcr effector of TRD.
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In memoriam Dorothea Bennett 1929-1990.
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Animals↗
Two-dimensional gel analysis of complex DNA families: methodology and apparatus.
We describe a reproducible protocol for the analysis of individual members of complex mammalian gene families by gel fractionation in two dimensions within a specially designed, easily built electrophoretic apparatus. We have used this protocol to resolve the family of mouse H-2 class I genes, with approximately 30 members, as well as two different families of endogenous retroviral-like sequences, each of which has approximately 180 members dispersed throughout the genome. The results demonstrate the feasibility of using this protocol for rapid, whole genome analysis of individual animals and cell lines. Two-dimensional DNA analysis of highly repeated retroviral-like DNA families could be applied to genetic mapping and cloning experiments as well as to obtaining whole genome fingerprints in the analysis of somatic cell hybrid lines that contain a subset of chromosomes from the genome of interest.
DNA Restriction Enzymes↗
Genetic exchange across a paracentric inversion of the mouse t complex.
Mouse t haplotypes are distinguished from wild-type forms of chromosome 17 by four nonoverlapping paracentric inversions which span a genetic distance of 20 cM. These inversion polymorphisms are responsible for a 100-200-fold suppression of recombination which maintains the integrity of complete t haplotypes and has led to their divergence from the wild-type chromosomes of four species of house mice within which t haplotypes reside. As evidence for the long period of recombinational isolation, alleles that distinguish all t haplotypes from all wild-type chromosomes have been established at a number of loci spread across the 20-cM variant region. However, a more complex picture emerges upon analysis of other t-associated loci. In particular, "mosaic haplotypes" have been identified that carry a mixture of wild-type and t-specific alleles. To investigate the genetic basis for mosaic chromosomes, we conducted a comprehensive analysis of eight t complex loci within 76 animals representing 10 taxa in the genus Mus, and including 23 previously characterized t haplotypes. Higher resolution restriction mapping and sequence analysis was also performed for alleles at the Hba-ps4 locus. The results indicate that a short tract of DNA was transferred relatively recently across an inversion from a t haplotype allele of Hba-ps4 to the corresponding locus on a wild-type homolog leading to the creation of a new hybrid allele. Several classes of wild-type Hba-ps4 alleles, including the most common form in inbred strains, appear to be derived from this hybrid allele. The accumulated data suggest that a common form of genetic exchange across one of the four t-associated inversions is gene conversion at isolated loci that do not play a role in the transmission ratio distortion phenotype required for t haplotype propagation. The implications of the results pose questions concerning the evolutionary stability of gene complexes within large paracentric inversions and suggest that recombinational isolation may be best established for loci residing within a short distance from inversion breakpoints.
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A novel mouse chromosome 17 hybrid sterility locus: implications for the origin of t haplotypes.
The effects of heterospecific combinations of mouse chromosome 17 on male fertility and transmission ratio were investigated through a series of breeding studies. Animals were bred to carry complete chromosome 17 homologs, or portions thereof, from three different sources-Mus domesticus, Mus spretus and t haplotypes. These chromosome 17 combinations were analyzed for fertility within the context of a M. domesticus or M. spretus genetic background. Two new forms of hybrid sterility were identified. First, the heterospecific combination of M. spretus and t haplotype homologs leads to complete male sterility on both M. spretus and M. domesticus genetic backgrounds. This is an example of symmetrical hybrid sterility. Second, the presence of a single M. domesticus chromosome 17 homolog within a M. spretus background causes sterility, however, the same combination of chromosome 17 homologs does not cause sterility within the M. domesticus background. This is a case of asymmetrical hybrid sterility. Through an analysis of recombinant chromosomes, it was possible to map the M. domesticus, M. spretus and t haplotype alleles responsible for these two hybrid sterility phenotypes to the same novel locus (Hybrid sterility-4). Previous structural studies had led to the hypothesis that the ancestral t haplotype originated through an introgression event from M. spretus or a related species. If this were true, one might expect that (1) M. spretus homologs would be transmitted at a non-Mendelian ratio within the M. domesticus background, and (2) t haplotypes would be transmitted at a ratio closer to Mendelian within the M. spretus background.(ABSTRACT TRUNCATED AT 250 WORDS)
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Escape from genomic imprinting at the mouse T-associated maternal effect (Tme) locus.
Genomic imprinting occurs at the paternally inherited allele of the mouse T-associated maternal effect (Tme) locus. As a consequence, maternal transmission of a functional Tme gene is normally required for viability and individuals that receive a Tme-deleted chromosome (Thp or tlub2) from their mother die late in gestation or shortly thereafter. Here we report that a rearranged paternally derived chromosome duplicated for the Tme locus can act to rescue animals that have not received a maternal copy of the Tme locus. Unexpectedly, all rescued animals display an abnormal short/kinky tail phenotype. Somatic transfer of genomic imprinting between homologs by means of a transvection-like process between paired Tme and T loci is proposed as a model to explain the results obtained.
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At the crossroads of developmental genetics: the cloning of the classical mouse T locus.
The discovery, more than 60 years ago, of a mutant mouse with a short tail led to the birth of the new field of developmental genetics. Over the years since, numerous investigators have probed the biology of the original short-tail mutation at the T locus, as well the naturally-occurring t haplotypes that were uncovered as a result of their interaction with this mutation. Although the T locus ranks among the best characterized developmental loci in the mouse, it was not among the first to be cloned. This situation has now been rectified with two recent reports from Herrmann, Lehrach and their colleagues. While the T locus is expressed uniquely in the embryonic tissues predicted from the mutant phenotype, the gene itself, as well as the predicted amino acid sequence of the T product, show no strong homology to any known sequence. For the moment, at least, the mystery behind the function of the T locus still awaits definitive resolution.
Animals↗
New reproductive technologies in the treatment of human infertility and genetic disease.
In this paper I will discuss three areas in which advances in human reproductive technology could occur, their uses and abuses, and their effects on society. First is the potential to drastically increase the success rate and availability of in vitro fertilization and embryo freezing. Second is the ability to perform biopsies on embryos prior to the onset of pregnancy. Finally, I will consider the adding or altering of genes in embryos, commonly referred to as "genetic engineering". As new reproductive technologies pass from experimental models into the potential for medical utilization, I believe that it will be important for lawmakers everywhere to avoid the impulse to outlaw procedures that a society believes to be 'unnatural' at a first glance. Rather, I would hope that they can respond thoughtfully with legislation that serves two purposes--to protect the rights of couples to overcome infertility or to reduce the risk of genetic disease in their children-to-be, and more importantly, to protect children-to-be from the abuses that could result from some of the practices that I will discuss.
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Molecular cloning of the t complex responder genetic locus.
Although mouse t haplotypes carry recessive mutations causing male sterility and embryonic lethality, they persist in wild mouse populations via male transmission ratio distortion (TRD). Genetic evidence suggests that at least five t-haplotype-encoded loci combine to cause TRD. One of these loci, called the t complex responder (Tcr), is absolutely required for any deviation from Mendelian segregation to occur. A candidate for the Tcr gene has previously been identified. Evidence that this gene represents Tcr is its localization to the appropriate genomic subregion and testis-specific expression pattern. Here, we report the molecular cloning of the region between recombinant chromosome breakpoints defining the Tcr locus. These results circumscribe Tcr to a 150- to 220-kb region of DNA, including the 22-kb candidate responder gene. This gene and two other homologs were created by large genomic duplications, each involving segments of DNA 10-fold larger than the individual genes.
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