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E Zuckerkandl

Publications and source records attributed to E Zuckerkandl.

At least 19 recordsLinked to original sources
PubMed1992

Revisiting junk DNA.

The distribution of functions within genomes of higher organisms relative to processes that lead to the spread of mutations in populations is examined in its general outlines. A number of points are enumerated that collectively put in question the concept of junk DNA: the plausible compatibility of DNA function with rapid substitution rates; the likelihood of superimposed functions along much of eukaryotic DNA; the potential for a merely conditional functionality in sequence repeats; the apparent adoption of macromolecular waste as a strategy for maintaining a function without selective grooming of individual sequence repeats that carry out the function; the likely requirement that any DNA sequence must be "polite" vis-'a-vis (compatible with) functional sequences in its genomic environment; the existence in germ-cell lineages of selective constraints that are not apparent in populations of individuals; and the fact that DNA techtonics - the appearance and disappearance of genomic DNA - are not incompatible with function. It is pointed out that the inverse correlation between functional constraints and rates of substitution cannot be claimed to be pillar of the neutral theory, because it is also predicted from a selectionist viewpoint. The dispensability of functional structures is brought into relation with the concept of reproductive sufficiency the survivability of genotypes in the absence of fitter alleles.

Animals↗
PubMed1991

Free left arms as precursor molecules in the evolution of Alu sequences.

The dimeric Alu molecule of human and other primates is composed of a left and a right arm that are very similar but show characteristic differences. If the Alu sequence has arisen through the fusion of monomeric precursor molecules, the traces of such precursor genes are expected still to be present in contemporary primate DNA. We report finding seven independent human DNA sequences that qualify as descendants of a left-arm precursor gene. Some characteristics in primary and secondary structures of these sequences are described.

Animals↗
PubMed1991

Quantitative protein changes in metastatic versus primary epithelial ovarian carcinoma.

Primary and metastatic ovarian carcinomas from six patients were obtained during primary exploratory laparotomy. Tumor cells were synthetically radiolabeled with [35S]methionine. Radiolabeled cellular proteins of the primary and metastatic cells were examined by two-dimensional polyacrylamide gel electrophoresis followed by autoradiography. Computer assisted analysis of the resultant autoradiograms revealed that the amounts of only two proteins, p35 and p36, were consistently and significantly decreased in the metastatic tumor cells. No other consistent differences in protein synthesis between primary and metastatic tumors were detected.

Down-Regulation↗
PubMed1989

Maintenance of function without selection: Alu sequences as "cheap genes".

Continued insertion into the genome of functional Alu sequences is expected to compensate for the functional eclipse of older sequences attributable to structural adulteration and can be presumed to establish a renewable store of functional sequences at a relatively elevated numerical level. This store of functional sequences could be maintained at almost no selective cost. A strategy of maintaining function in multiple sequence copies with selection limited to a very few master (source) sequences may be resorted to also by other types of DNA sequences that are generated repeatedly during evolution and that are spread over many sectors of the genome.

Animals↗
PubMed1988

Generation of high specificity of effect through low-specificity binding of proteins to DNA.

It is proposed that proteins can bind with relatively low-affinity and specificity to multiple sites, defined as sequence motifs, on polynucleotide chains, and that such binding can collectively be turned into high-affinity, high-specificity binding through cooperative effects, especially when the sequence motifs recur periodically. The selection of individual nucleotides has in general been thought to be the condition of the existence and conservation of function in most of the noncoding sequences. This condition seems unnecessary. Calculations are presented as a step in the direction of giving credibility to a model of stable gene repression.

DNA↗
PubMed1988

Concentration-affinity equivalence in gene regulation: convergence of genetic and environmental effects.

It is proposed that equivalent phenotypic effects can be obtained by either structural changes in macromolecules involved in gene regulation or changes in activity of the structurally unaltered macromolecules. This equivalence between changes in activity (concentration) and changes in structure can come into play within physiologically plausible limits and seems to represent an important interface between environment and genome--namely, between environmentally determined and genetically determined gene expression. The equivalence principle helps explain the appearance of phenocopies. It also points to a general pathway favorable to the occurrence, during evolution, of frequent episodes corresponding to Waddington's genetic assimilation and is likely to represent one component of the system responsible for the high frequency of recurrence of parallel evolution.

Biological Evolution↗
PubMed1988

Down-regulation of an abundant cellular protein associated with tumor progression.

Alteration of gene expression in neoplastic cells can be detected by two-dimensional gel electrophoresis. This study reports the altered synthesis of an abundant cellular protein, p29, accompanying tumorigenic transformation of immortalized fibroblasts induced by transfection with oncogenic DNA. Cell lines derived from morphologically transformed foci synthesized p29 at 60-75% reduced levels compared with untransformed parental cells. Upon inoculation into syngeneic immunocompetent animals, transformed cells gave rise to tumors which were excised and established in culture. The amount of p29 in both focal and tumor-derived lines was inversely correlated with the latent period for tumor formation. In cell lines with a tumor latency of 12-20 days, the level of p29 was decreased by 90-99%. In rapidly tumorigenic cells with a short latency (3-6 days), p29 synthesis was not detectable. These data demonstrate that p29 may be a sensitive and reliable marker for tumor progression of fibroblasts.

Animals↗
PubMed1987

On the molecular evolutionary clock.

The conceptual framework surrounding the origin of the molecular evolutionary clock and circumstances of this origin are described. In regard to the quest for the best available molecular clocks, a return to protein clocks is conditionally recommended. On the basis of recent data and certain considerations, it is pointed out that the realm of neutrality in evolution is probably less extensive than is now commonly thought, in the three distinct senses of the term neutrality--neutrality as nonfunctionality of mutations, neutrality as equifunctionality of mutations, and neutrality as a mode of fixation of mutations. The possibility is raised that complex sets of interacting components forming a system that is bounded with respect to its environment may quite generally display an intrinsic trend to a quasi-clockwise evolutionary behavior.

Biological Evolution↗
PubMed1986

Quantitative protein profiling: determining lexotypes.

The lexotype of a cell is defined as a set of quantitative characters of its informational macromolecular gene products, notably proteins, as observed under specified environmental conditions. This definition can be applied to cells in several ways that need to be distinguished. It can refer to the protein lexotype, to RNA lexotypes; to the steady-state lexotype, synthesis lexotype, functional protein lexotype; to the in situ lexotype and standard-environment lexotype. When used without qualification, the term lexotype may be applied to the standard-environment, steady-state protein lexotype. Some difficulties that currently limit our ability to determine lexotypes are assessed. Reasons are given why abnormal cellular states, such as states of disease, should often be characterizable by means of protein markers not themselves involved in the disease process and why one expects to find markers in tissues other than the one in which a certain pathological process may be anticipated to occur. There are three routes through which biological systems can produce secondary protein markers, namely through gene regulatory chains, through chromosomal gene linkage, and through "physiological linkage" of genes. The partly stable, partly shifting, yet defined relations between tissue lexotypes are considered. A number of potentially important fields of application of rigorous quantitative analyses of protein profiles are listed. One particular use of the technology is to investigate a hypothesis linking aging to degenerative diseases with late onset. According to this hypothesis, such diseases appear in later life as the cellular concentration of the active form of a protein passes a certain threshold in the course of the aging process.

Aging↗
PubMed1986

Age-dependent changes in proteins of Drosophila melanogaster.

Several molecular theories of aging postulate that there are age-dependent changes in gene expression and that these changes contribute to the reduction in the viability of senescent cells. High-resolution, semiautomated, quantitative two-dimensional gel electrophoresis of many soluble proteins was used to test this hypothesis in Drosophila. Two-dimensional protein gel patterns were analyzed for each of three age groups of [(35)S]methionine-labeled adult male Drosophila melanogaster, which, except for their spermatocytes, consist entirely of fixed postmitotic cells. Seven relatively abundant polypeptides expressed in middle-aged (28-day-old) flies were absent in both young(10-day-old) and old (44-day-old) flies. Quantitative analyses of an additional 100 polypeptides were carried out by computer-assisted microdensitometry of fluorograms of the gel preparations. These analyses revealed a significant age-related heterogeneity in the quantitative distribution of radiolabel in these proteins. The data indicate that the qualitative pattern of gene expression is identical in young and old flies, but that profound quantitative changes occur in the expression of proteins during the Drosophila life-span.

Aging↗
PubMed1986

Polite DNA: functional density and functional compatibility in genomes.

Certain as yet poorly defined functions of DNA appear to involve collectively domain-sized sequences. It is proposed that most sequence segments within a domain may be either functionally superfluous or instrumental, depending on how many related sequences are present in the domain. When redundant and functionally dispensable, such DNA segments presumably still have to conform to compositional or sequence-motif patterns that characterize the domain. In its relations with neighboring sequences, such DNA is required to be "polite." Polite DNA is DNA that, without being crucially involved in function, is subject to constraints of conformity and, through its base composition, respects a function for which it is not required. This concept is developed by contrasting the distribution of specific and general functions over DNA with this distribution as found in proteins and by distinguishing functional compatibility from pivotal functionality. The sequence constraints to which heterochromatin as well as, apparently, long interspersed repetitive sequences are known to be subject seem to imply that DNA, even when it does not carry out a pivotal function, is indeed, at the very least, required to be polite.

Animals↗
PubMed1976

Gene control in eukaryotes and the c-value paradox "excess" DNA as an impediment to transcription of coding sequences.

Ways in which control of gene activity may lead to the observed high DNA content per haploid eukaryote genome are examined. It is proposed that deoxyribonucleoprotein (DNP) acts as a barrier to transcription at two distinct structural levels. At the lower level, melting of the nucleosome supercoil (quaternary structure) and of the nucleosomes (tertiary structure) might be brought about by the process of transcription itself. After unwinding the barrier section, the polymerase would eventually reach the structural gene. The transcripts of noncoding sequences, at least as far as their "unique" sequence components are concerned, may thus have filled their main function through the very process of transcription. The possibility of an inverse relationship between the length of the DNP barrier and the rates of transcription of the coding sequences is to some extent supported by available data. Different modes of coordination between the transcription of mRNA and of hnRNA from a single functional unit of gene action (funga) are considered. An analysis of gene control at high structural levels of DNP is made on the basis of other data, in relation to the concepts of eurygenic and stenogenic control. The concept of a euryon is introduced, namely of a set of linked fugas under common eurygenic control. Structure of order higher than quaternary can be inferred to exist in larger chromomeres of polytene chromosomes and in corresponding sections of ordinary chromosomes. Only moderate amounts of highest order interphase euchromatic structure are likely to be able to be accomodated in average chromomeres and none in very thin chromomeres. Puffs are interpreted as the melting of highest order interphase structure, and the absence of puffs during transcription as the absence of this highest order structure in the resting state of the chromomeres. Genes that are constantly active in all tissues may dispense with highest order interphase structure and with the corresponding control mechanism, and the fugas involved thus may not puff. Puffs, large chromomeres and highest order interphase euchromatic DNP structure seem to be correlated with genes that need to be transcribed only under certain developmental conditions. It is proposed that the function of high order structure is to sequester genetic material, namely mainly controller sequences. Since such high order structure, in most cases, would be built up to house the controller dependencies of just one structural gene, the amount of DNA per structural gene needed for gene control would be considerable, and the concept, if correct, would go a long way towards explaining the c-value paradox ("excess" DNA in eukaryotes). In eurygenic determination, the high order structure is thought to be conditioned for melting or to actually melt to an intermediate level of structure. From there, stenogenic control, leading to transcription, is considered to carry the melting process further to yet lower structural levels...

Animals↗
PubMed1976

Evolutionary processes and evolutionary noise at the molecular level. II. A selectionist model for random fixations in proteins.

On account, notably, of a competition between different component functions for individual sites in polypeptide chains, each protein molecule represents a functional compromise, with some functions optimized, but the overall state of the molecule "suboptimal". The proposal is made that the selection coefficient relating to a protein molecule under given conditions can in principle be broken down into partial selection coefficients relevant to the different functions that the molecule carries out. At general-function sites, each fixation improves some function, while others deteriorate, at first nonsignificantly, and the overall adaptive state of the molecule fluctuates around its maximum. A selective mechanism is described whereby kaleidoscopic changes in primary structure at variable sites are indefinitely promoted, independently of any environmental changes and with the molecule remaining close to a state of maximal overall adaptation. The paradoxical aspect of this proposal is analyzed. The implication of specific functions in substitutions at general-function sites is noted. Further, it is shown that a certain category of changes in the internal environment of the organism can be integrated into the constant-environmental model for selection. Genetic sufficiency is considered a notion more adequate than genetic optimality for describing biological fitness and for providing a basis for the present model. On this basis selection occurs without genetic load. Multipolymorphism is one of the consequences. Several lines of evidence, in particular observations on polymorphism in deep sea organisms, seem to support the model. It is pointed out that it provides a theoretical foundation for a molecular evolutionary clock. The theoretical constancy of the clock depends on the constancy of functional density. The question of the evolution of functional density is examined. Comparisons of observed substitution frequencies with values expected on a random basis are rejected as a measure of the contribution to evolution of nondetermination. They are considered to reflect a hierarchy in the resistance of the molecules to different amino acid residues as substituents. A limited component of "true" randomness, again accompanied by selection, is on the other hand provided by the model. Most amino acid substitutions are considered evolutionary noise, even though noise compatible with selection. It is proposed that evolutionary significant substitutions may be identified by monitoring changes in functional density and weighted functional density.

Alleles↗