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PubMed1972

Segmental aneuploidy and the genetic gross structure of the Drosophila genome.

By combining elements of two Y-autosome translocations with displaced autosomal breakpoints, it is possible to produce zygotes heterozygous for a deficiency for the region between the breakpoints, and also, as a complementary product, zygotes carrying a duplication for precisely the same region. A set of Y-autosome translocations with appropriately positioned breakpoints, therefore, can in principle be used to generate a non-overlapping set of deficiencies and duplications for the entire autosomal complement.-Using this method, we have succeeded in examining segmental aneuploids for 85% of chromosomes 2 and 3 in order to assess the effects of aneuploidy and to determine the number and location of dosage-sensitive loci in the Drosophila genome (Figure 5). Combining our data with previously reported results on the synthesis of Drosophila aneuploids (see Lindsley and Grell 1968), the following generalities emerge.-1. The X chromosome contains no triplo-lethal loci, few or no haplo-lethal loci, at least seven Minute loci, one hyperploid-sensitive locus, and one locus that is both triplo-abnormal and haplo-abnormal. 2. Chromosome 2 contains no triplo-lethal loci, few or no haplo-lethal loci, at least 17 Minute loci, and at least four other haplo-abnormal loci. 3. Chromosome 3 contains one triplo-lethal locus that is also haplo-lethal, few or no other haplo-lethal loci, at least 16 Minute loci, and at least six other haplo-abnormal loci. 4. Chromosome 4 contains no triplo-lethal loci, no haplo-lethal loci, one Minute locus, and no other haplo-abnormal loci.-Thus, the Drosophila genome contains 57 loci, aneuploidy for which leads to a recognizable effect on the organism: one of these is triplo-lethal and haplo-lethal, one is triplo-abnormal and haplo-abnormal, one is hyperploid-sensitive, ten are haplo-abnormal, 41 are Minutes, and three are either haplo-lethals or Minutes. Because of the paucity of aneuploid-lethal loci, it may be concluded that the deleterious effects of aneuploidy are mostly the consequence of the additive effects of genes that are slightly sensitive to abnormal dosage. Moreover, except for the single triplo-lethal locus, the effects of hyperploidy are much less pronounced than those of the corresponding hypoploidy.

Aneuploidy↗
PubMed1991

Structural and genetic analysis of electrostatic and other interactions in bacteriophage T4 lysozyme.

The lysozyme from bacteriophage T4 is being used as a model system to determine the roles of individual amino acids in the folding and stability of a typical globular protein. Such studies can provide quantitative information on the contributions made by different types of interactions including hydrogen bonds, hydrophobic interactions, salt bridges and disulphide bridges. To determine the contribution of long-range electrostatic interactions a combination of charge-change mutations was used to reduce the overall formal charge on T4 lysozyme at neutral pH from +9 to +1 units. Such changes in charge were found to have little effect on the stability of the molecule. Salt bridges engineered on the surface of the protein also were found to contribute little to stability. In contrast, the introduction of acidic groups designed to interact with the partial positive charges at the N-termini of alpha-helices consistently increased the stability of the protein. It is argued that this difference between electrostatic salt-bridge interactions and electrostatic 'helix-dipole' interactions lies in the entropic cost of bringing together the interacting partners. In an attempt to simplify the folding problem, and also to further investigate the helix propensity of different amino acids, a series of alanines was introduced within an alpha-helix of T4 lysozyme. The resultant protein not only folds normally but is also more stable than the wild-type enzyme, adding further support to recent evidence that alanine is a helix-favouring amino acid.

Electricity↗
PubMed1985

Comparison of distance matrices in studies of population structure and genetic microdifferentiation: quadratic assignment.

Questions concerning the relative effects of various evolutionary forces in molding the genetic variability exhibited by groups of human populations have typically been investigated by comparing a variety of genetic and cultural/historical "distance" matrices. A major methodological difficulty has been the lack of formal testing procedures with which to assess the degree of confirmation or disconfirmation of an estimated measure of relationship between such matrices. In this paper, we examine a very flexible matrix combinatorial procedure which generates statistical significance levels for correlational measures of pattern similarity between distance matrices. A recent generalization of the basic procedure to the three-matrix case allows questions concerning which of two matrices best fits a third matrix to be formally tested. Applications of these hypothesis testing and inference procedures to two separate sets of genetic, geographic, and cultural distance matrices illustrates their potential for finally solving a long-standing problem in anthropological genetics.

Anthropometry↗
PubMed1978

Cell-mediated lympholysis: examination of HLA genetic fine structure and complementation using cytotoxic lymphocytes.

Human cytotoxic lymphocytes (CTL), sensitized in vitro in one-way mixed lymphocyte cultures between two unrelated individuals, have been used to study target cell determinants. One pair of CTL shows strong cell-mediated lympholysis responses against the specific target cells as well as against third-party target cells obtained from unrelated individuals. Testing of sixty target cells shows a significant association between the two CTL with a correlation coefficient of 0.67 in the panel. The target determinant recognized by the CTL is not an HLA-A,B,C or D specificity, as defined by standard serological and cellular reagents. Segregation studies in a large family reveal that the new specificity defined by the CTL is controlled by HLA, and its recognition may be restricted by the HLA complex.

Cytotoxicity Tests, Immunologic↗
PubMed1989

Genetic and structural analysis of the ColE1 Rop (Rom) protein.

Repressor of primer (Rop) is a small dimeric protein that participates in the mechanism that controls the copy number of plasmid of the ColE1 family by increasing the affinity between two complementary RNAs. The Rop dimer is a bundle of four tightly packed alpha-helices that are held together by hydrophobic interactions. We have systematically altered, by site directed mutagenesis, most of the solvent exposed amino acids of the Rop bundle and we have identified the alterations that cause a decrease of the activity of the regulatory molecule. We conclude that Rop folding is rather insensitive to amino acid substitutions and to other mutations as drastic as deletions and insertions. Looking along the 2-fold symmetry axis the amino acid side chains whose alterations affect the function of Rop are all located on one side of the molecule. Furthermore they are clustered at the extremities of the alpha-helix bundle, the only exception being the aromatic ring of Phe-14.

Amino Acid Sequence↗
PubMed1991

A genetic and structural analysis of the yeast Vps15 protein kinase: evidence for a direct role of Vps15p in vacuolar protein delivery.

The yeast VPS15 gene encodes a novel protein kinase homolog that is required for the sorting of soluble hydrolases to the yeast vacuole. In this study, we extend our previous mutational analysis of the VPS15 gene and show that alterations of specific Gps15p residues, that are highly conserved among all protein kinase molecules, result in the biological inactivation of Vps15p. Furthermore, we demonstrate here that short C-terminal deletions of Vps15p result in a temperature-conditional defect in vacuolar protein sorting. Immediately following the temperature shift, soluble vacuolar hydrolases, such as carboxypeptidase Y and proteinase A, accumulate as Golgi-modified precursors within a saturable intracellular compartment distinct from the vacuole. This vacuolar protein sorting block is efficiently reversed when mutant cells are shifted back to the permissive temperature; the accumulated precursors are rapidly processed to their mature forms indicating that they have been delivered to the vacuole. This rapid and efficient reversal suggests that the accumulated vacuolar protein precursors were present within a normal transport intermediate in the vacuolar protein sorting pathway. In addition, this protein delivery block shows specificity for soluble vacuolar enzymes as the membrane protein, alkaline phosphatase, is efficiently delivered to the vacuole at the non-permissive temperature. Interestingly, the C-terminal Vps15p truncations are not phosphorylated in vivo suggesting that the phosphorylation of Vps15p may be critical for its biological activity at elevated temperatures. The rapid onset and high degree of specificity of the vacuolar protein delivery block in these mutants suggests that the primary role of Vps15p is to regulate the sorting of soluble hydrolases to the yeast vacuolar compartment.

Fungal Proteins↗
PubMed1993

Evolutionary conservation of the mouse apolipoprotein e-c1-c2 gene cluster: structure and genetic variability in inbred mice.

The human apolipoprotein E (APOE), APOC1, pseudo APOC1 (APOC1'), and APOC2 genes are clustered within 48 kb on the long arm of chromosome 19. A mouse Apoe cDNA probe was used to isolate overlapping cosmid clones from a cosmid library of the C57BL/Rij inbred mouse strain. These clones were investigated for the presence of the Apoc1 and Apoc2 genes by heterologous hybridization. Our results show that the Apoe-c1-c2 gene cluster is conserved in the mouse. In line with evolutionary data, the mouse lacks the equivalent of APOC1'. These data were confirmed using a mouse Apoc2 cDNA clone, and surprisingly the cDNA clone isolated here was 965 bp in size, which is on average 450 bp longer than other APOC2 cDNAs described so far. Correspondingly, the Apoc2 gene occupies an unusually large genomic region, due to an extended 5' end. Interestingly, a variable number of tandem repeat (VNTR) in the third intron of the human APOC2 gene shows a high sequence homology and is located at the identical position in the mouse gene. Despite the high copy number of this VNTR (27 or 34 copies) only two variants were found among 11 different inbred strains. With the aid of six restriction fragment length variations in this gene cluster only two different haplotypes could be deduced, indicating that the Apoe-c1-c2 gene cluster is highly conserved in the inbred strains that were studied.

Animals↗
PubMed1999

Genetic and structural characterization of the human mitochondrial inner membrane translocase.

Translocation of nuclear-encoded mitochondrial preproteins is mediated by translocases in the outer and inner membranes. In the yeast Saccharomyces cerevisiae, translocation of preproteins into the matrix requires the membrane proteins Tim23, Tim17 and Tim44, which drive translocation in cooperation with mtHsp70 and its co-chaperone Mge1p. We have cloned and functionally analyzed the human homologues of Tim17, Tim23 and Tim44. In contrast to yeast, two TIM17 genes were found to be expressed in humans. TIM44, TIM23 and TIM17a genes were mapped to chromosomes 19p13.2-p13.3, 10q11. 21-q11.23 and 1q32. The TIM17b gene mapped to Xp11.23, near the fusion point where an autosomal region was proposed to have been added to the "ancient" part of the X chromosome about 80-130 MY ago. The primary sequences of the two proteins, hTim17a and hTim17b, are essentially identical, significant differences being restricted to their C termini. They are ubiquitously expressed in fetal and adult tissues, and both show expression levels comparable to that of hTim23. Biochemical characterization of the human Tim components revealed that hTim44 is localized in the matrix and, in contrast to yeast, only loosely associated with the inner membrane. hTim23 is organized into two distinct complexes in the inner membrane, one containing hTim17a and one containing hTim17b. Both TIM complexes display a native molecular mass of 110 kDa. We suggest that the structural organization of TIM23.17 preprotein translocases is conserved from low to high eukaryotes.

Adult↗
PubMed1991

Structural and genetic properties of the Eb recombinational hotspot in the mouse.

The Eb gene of the mouse contains a recombinational hotspot which plays a predominant role in meiotic crossing-over within the I region of the mouse major histocompatibility complex (MHC). The nucleotide sequences of five recombinants derived from H-2k/H-2b heterozygotes at the Eb locus placed the sites of recombination in each recombinant haplotype within a 2.9 kilobase (kb) segment located fully within the second intron of the Eb gene. Further resolution of the crossover sites was not possible since the nucleotide sequences of the parental and recombinant haplotypes are identical within this segment. The molecular characterization of these five recombinants considered in conjunction with three previously reported intra-Eb recombinants indicates that there are at least two distinct sites of recombination within the Eb recombinational hotspot. In a related study, an examination of the nucleotide sequence of the H-2p allele of the Eb gene revealed a major genetic rearrangement in the 5' half of the intron in this haplotype. A 597 base pair (bp) nucleotide sequence found in the H-2p haplotype is replaced by a 1634 bp segment found in the H-2b and H-2k haplotypes. Sequence analysis of this 1634 bp segment shows strong nucleotide sequence similarity to retroposon long terminal repeat (LTR), env, and pol genes indicating that this segment of the second intron has evolved through retroposon insertion. The location of these retroposon sequences within the 2.9 kb recombination segment defined by the five H-2k/H-2b recombinant haplotypes suggests a possible relationship between these retroviral elements and site-specific recombination within the second intron of the Eb gene.

Animals↗
PubMed1993

Molecular structure and genetic regulation of SFA, a gene responsible for resistance to formaldehyde in Saccharomyces cerevisiae, and characterization of its protein product.

A 3.7 kb DNA fragment of yeast chromosome IV has been sequenced that contains the SFA gene which, when present on a multi-copy plasmid in Saccharomyces cerevisiae, confers hyper-resistance to formaldehyde. The open reading frame of SFA is 1158 bp in size and encodes a polypeptide of 386 amino acids. The predicted protein shows strong homologies to several mammalian alcohol dehydrogenases and contains a sequence characteristic of binding sites for NAD. Overexpression of the SFA gene leads to enhanced consumption of formaldehyde, which is most probably the reason for the observed hyper-resistance phenotype. In sfa::LEU2 disruption mutants, sensitivity to formaldehyde is correlated with reduced degradation of the chemical. The SFA gene shares an 868 bp divergent promoter with UGX2 a gene of yet unknown function. Promoter deletion studies with a SFA promoter-lacZ gene fusion construct revealed negative interference on expression of SFA by upstream sequences. The upstream region between positions -145 and -172 is totally or partially responsible for control of inducibility of SFA by chemicals such as formaldehyde (FA), ethanol and methyl methanesulphonate. The 41 kDa SFA-encoded protein was purified from a hyper-resistant transformant; it oxidizes long-chain alcohols and, in the presence of glutathione, is able to oxidize FA. SFA is predicted to code for a long-chain alcohol dehydrogenase (glutathione-dependent formaldehyde dehydrogenase) of the yeast S. cerevisiae.

Alcohol Dehydrogenase↗
PubMed1984

Physical structure and genetic expression of the sulfonamide-resistance plasmid pLS80 and its derivatives in Streptococcus pneumoniae and Bacillus subtilis.

The 10-kb chromosomal fragment of Streptococcus pneumoniae cloned in pLS80 contains the sul-d allele of the pneumococcal gene for dihydropteroate synthase. As a single copy in the chromosome this allele confers resistance to sulfanilamide at 0.2 mg/ml; in the multicopy plasmid it confers resistance to 2.0 mg/ml. The sul-d mutation was mapped by restriction analysis to a 0.4-kb region. By the mechanism of chromosomal facilitation, in which the chromosome restores information to an entering plasmid fragment, a BamHI fragment missing the sul-d region of pLS80 established the full-sized plasmid, but with the sul-s allele of the recipient chromosome. A spontaneous deletion beginning approximately 1.5 kb to the right of the sul-d mutation prevented gene function, possibly by removing a promoter. This region could be restored by chromosomal facilitation and be demonstrated in the plasmid by selection for sulfonamide resistance. Under selection for a vector marker, tetracycline resistance, only the deleted plasmid was detectable, apparently as a result of plasmid segregation and the advantageous growth rates of cells with smaller plasmids. When such cells were selected for sulfonamide resistance, the deleted region returned to the plasmid, presumably by equilibration between the chromosome and the plasmid pool, to give a low frequency (approximately 10(-3) of cells resistant to sulfanilamide at 2.0 mg/ml. Models for the mechanisms of chromosomal facilitation and equilibration are proposed. Several derivatives of pLS80 could be transferred to Bacillus subtilis, where they conferred resistance to sulfanilamide at 2 mg/ml, thereby demonstrating cross-species expression of the pneumococcal gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacillus subtilis↗
PubMed1988

Structural and genetic features of human leukocytic antigen class II elements associated with rheumatoid arthritis.

Analysis of individual human leukocyte antigen (HLA) genes associated with rheumatoid arthritis was performed using oligonucleotide probes to identify putative susceptibility genes highly associated with disease. Among DR4-positive rheumatoid arthritis patients, two distinct DR-beta genes, Dw4 and Dw14, appear to be individual susceptibility alleles. Linked HLA genes at the DQ locus do not appear to contribute to this genetic risk. Among non-DR4 rheumatoid arthritis patients, a specific DNA sequence was identified that is shared by the Dw14 susceptibility gene and a majority of the non-DR4 rheumatoid arthritis patients. This sequence defines a specific small genetic element encoding a "Dw14 epitope" that appears to be a rheumatoid arthritis-associated risk factor indicative of a common genetic pathway in both DR4 and non-DR4-associated disease.

Arthritis, Rheumatoid↗

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