Dispersion of alpha-like globin genes of the mouse to three different chromosomes.
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Animals↗
Biomedical subjects
P Leder
Publications and source records attributed to P Leder.
Multiple immunoglobulin switch region homologies outside the heavy chain constant region locus.
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Animals↗
Variable amplification of immunoglobulin lambda light-chain genes in human populations.
The human lambda immunoglobulin locus displays a series of restriction fragment length polymorphisms that are readily detected in small populations of normal individuals. Similar polymorphisms appear in populations of wild mice, suggesting that the lambda locus is subject to rapid variation within a single species. Here we show that the polymorphisms seen in the human lambda locus seem to have arisen from unequal meiotic crossing over, altering the number of lambda from as few as six to as many as nine per haploid genome. This expansion and contraction in the number of human lambda genes is significant in that it may affect an individual's capacity to produce variation among lambda light chain genes.
Base Composition↗
A conserved sequence in the immunoglobulin J kappa-C kappa intron: possible enhancer element.
Several functionally important genetic elements (such as the TATA box, mRNA splice sequences, poly(A) addition signal) were first detected as short segments of unexplained sequence homology within non-coding regions of different genes. A short region of unknown sequence in the intron between the human J kappa and C kappa immunoglobulin coding regions was found to be sufficiently homologous to the corresponding segment of the mouse gene to form stable heteroduplexes. Although no specific function has yet been definitely ascribed to this region (which we call the kappa intron conserved region, or KICR), some functional significance has been inferred from the findings that (1) activation of B lymphocytes induces a DNase hypersensitivity site in this region and (2) deletions including this region reduce expression of kappa genes introduced into lymphoid cells. To delineate the KICR more precisely and to test the generality of the sequence conservation in a third species, we have sequenced this region of the human and mouse genes and have examined the corresponding region of a recently cloned rabbit kappa gene. We find a segment of about 130 base pairs (bp) that shows striking conservation in all three species, demonstrating homology significantly higher than within the C kappa coding region itself. Two short sequences from the J kappa-C kappa intron that were noted by other investigators to be homologous to proposed 'enhancer' sequences both lie within the conserved region.
Animals↗
A variant translocation places the lambda immunoglobulin genes 3' to the c-myc oncogene in Burkitt's lymphoma.
Most translocations that occur in Burkitt's lymphoma involve movement of part of chromosome 8, containing the c-myc gene, from its normal position to the immunoglobulin heavy-chain locus on chromosome 14. The genes are often joined at their 5' ends in opposite transcriptional directions. However, a significant minority of Burkitt translocations involve the light-chain loci on chromosome 2 (kappa) or 22 (lambda). We have characterized one of these from a European-derived cell line (IARC-BL37) that carries an 8;22 translocation. Here the translocation has joined the 5' portion of the lambda light-chain locus to the 3' portion of the c-myc gene at a position about 7 kilobases from the normal c-myc promoters. The translocation is reciprocal and relatively conservative, involving the loss of only 21 base pairs from the site of recombination. This translocation allows us to orient the lambda genes with respect to the centromere of chromosome 22 and to predict the orientation of other translocations involving these chromosomal segments. The 3' translocation is accompanied by an increased level of c-myc transcripts, especially that derived from a normally under-used c-myc promoter.
Burkitt Lymphoma↗
Functional role for c-myc in mitogenic response to platelet-derived growth factor.
In BALB/c-3T3 cells, expression of the c-myc gene is stimulated by platelet-derived growth factor (PDGF). Using mouse mammary tumour virus promoter: c-myc recombinant plasmids, 3T3 sublines were constructed in which hydrocortisone was the primary determinant of myc mRNA content. The c-myc gene product is an intracellular mediator of the growth response to PDGF though probably not the only one. Both the human and the mouse c-myc genes stimulate clonal growth of 3T3 cells in PDGF-free medium suggesting new strategies for analysis of oncogenes which do not function in focus formation assays.
Animals↗
High-affinity binding site for a specific nuclear protein in the human IgM gene.
Proteins binding to specific regions of DNA with high affinity frequently govern or regulate reactions at the gene level. We have identified a high-affinity binding site in the immunoglobulin mu gene that binds a specific nuclear protein, and have now characterized it fully using nuclear factor 1 (NF-1), a protein purified from the nuclei of HeLa cells and required for the in vitro replication of adenovirus (Ad) DNA. NF-1 protects a 25-base pair (bp) double-stranded segment of DNA which shares a consensus sequence, 5' TGGA/CNNNNNGCCAA 3', with similar binding sites in the Ad-5 terminal repeat and the human c-myc gene. Although this site differs from the enhancer region, a biological function is suggested by the fact that it is DNase I hypersensitive in immunoglobulin-producing lymphoblastoid cells. The binding site for the NF-1 protein in the mu gene, by analogy with the site in the Ad-5 terminal repeat, may represent one component of a cellular origin of replication; alternatively, it may be responsible for the activation of the chromatin in this region.
Base Sequence↗
An inherited limb deformity created by insertional mutagenesis in a transgenic mouse.
We have created an insertional mutation that leads to a severe defect in the pattern of limb formation in the developing mouse. The novel recessive mutation is phenotypically identical and non-complementary to two previously encountered limb deformity mutations, and is closely linked to a dominant mutation that gives rise to a related limb dysmorphism. The inserted element thus provides a molecular genetic link with the control of pattern formation in the mammalian embryo.
Animals↗