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E Zuckerkandl

Publications and source records attributed to E Zuckerkandl.

At least 19 recordsLinked to original sources
PubMed2000

Cytosine deamination plays a primary role in the evolution of mammalian isochores.

DNA melting is rate-limiting for cytosine deamination, from which we infer that the rate of cytosine deamination should decline twofold for each 10% increase in GC content. Analysis of human DNA sequence data confirms that this is the case for 5-methylcytosine. Several lines of evidence further confirm that it is also the case for unmethylated cytosine and that cytosine deamination causes the majority of all C-->T and G-->A transitions in mammals. Thus, cytosine deamination and DNA base composition each affect the other, forming a positive feedback loop that facilitates divergent genetic drift to high or low GC content. Because a 10 degrees C increase in temperature in vitro increases the rate of cytosine deamination 5. 7-fold, cytosine deamination must be highly dependent on body temperature, which is consistent with the dramatic differences between the isochores of warm-blooded versus cold-blooded vertebrates. Because this process involves both DNA melting and positive feedback, it would be expected to spread progressively (in evolutionary time) down the length of the chromosome, which is consistent with the large size of isochores in modern mammals.

5-Methylcytosine↗
PubMed1999

Sectorial gene repression in the control of development.

Some evidence suggests that a number of regulator genes and gene clusters will likely be found to share with HOX complexes the property of being repressible ('superrepressible') through factor-driven conformational changes over whole sectors of chromatin, and of being assigned body locations in which they are either stably superrepressed or poised for transcription, according to determinants that act vectorially across a morphological zone. Such a subpopulation of regulator genes is expected to include, notably, genes governing developmental processes and might be thought to number, in mammals, between one hundred and several hundreds. When superrepressed, regulator genes are anticipated either to block programs of gene action or to permit these programs to unfold. To a significant extent, development would be determined by successive intersections of the paths of gene action deployment with superrepressed genes. These intersections, in cell lines advancing toward terminal differentiation, would be responsible for the progressive narrowing of the range of gene action programs potentially still available for later development. One implication of this model is that mosaic and regulative embryos are distinct merely by virtue of the time of onset of superrepression in their different cell lineages. Determination and transdetermination are considered to express the differential distribution over the genome of bound regulatory factors that function as molecular tools of superrepression, notably polycomb-group-like proteins. In turn, superrepressed genes are anticipated to be differentially distributed over cell types and thus to furnish a major framework for progressive differentiation and for the progressive limitation of the developmental potential of cells.

DNA↗
PubMed1997

Junk DNA and sectorial gene repression.

Transcriptional repression in eukaryotes often involves tens or hundreds of kilobase pairs, two to three orders of magnitude more than the bacterial operator/repressor model does. Classical repression, represented by this model, was maintained over the whole span of evolution under different guises, and consists of repressor factors interacting primarily with promoters and, in later evolution, also with enhancers. The use of much larger amounts of DNA in the other mode of repression, here called the sectorial mode ('superrepression'), results in the conceptual transfer of so-called junk DNA to the domain of functional DNA. This contribution to the solution of the c-value paradox involves perhaps 15% of genomic 'junk,' and encompasses the bulk of the introns, thought to fill a stabilizing role in sectorially repressed chromatin structures. In the case of developmental genes, such structures appear to be heterochromatoid in character. However, solid clues regarding general structural features of superrepressed terminal differentiation genes remain elusive. The competition among superrepressible DNA sectors for sectorially binding factors offers, in principle, a molecular mechanism for developmental switches. Position effect variegation may be considered an abnormal manifestation of normal processes that underly development and involve heterochromatoid sectorial repression, which is apparently required for local elimination or modulation of morphological features (morpholysis). Sectorial repression of genes participating either in development or in terminal differentiation is considered instrumental in establishing stable cell types, and provides a basis for the distinction between determination and cell type specification. The gamut of possible stable cell types may have been broadened by the appearance in evolution of heavy isochores. Additional types of relatively frequent GC-rich cis-acting DNA motifs may offer reiterated binding sites to factors endowed with a selective (though not individually strong) affinity for these motifs. The majority of sequence motifs thought to be used in superrepression need not be individually maintained by natural selection. It is re-emphasized that the dispensability of sequences is not an indicator of their nonfunctionality and that in many cases, along noncoding sequences, nucleotides tend to fill functions collectively, rather than individually.

Animals↗
PubMed1997

Neutral and nonneutral mutations: the creative mix--evolution of complexity in gene interaction systems.

Random drift, while indifferent to the functionality of the molecular features on which it acts, may nevertheless affect evolving molecular mechanisms. It can lead to functional novelty in either gene structure or regulation. In particular, a nearly neutral (in the sense of Ohta), somewhat deleterious mutation can result in a loss of efficiency in gene regulation, and this loss is expected at times to be compensated by a selected event of a particular type: the use of an additional regulatory factor. An accumulation of additional regulatory factors, implying a combination of events of drift and selection, can permit regulatory systems to achieve an increase in both specificity and complexity as mere byproducts of a particular repair process. Nearly neutral mutations thus may, at times, constitute a required pathway for increases in gene interaction complexity. The process seems to point to an inbuilt drive-built into the gene interaction system itself-toward the evolution of higher organisms. This is a matter worthy of experimental exploration, since the general foundations for the evolution of "higher" from "lower" organisms seems so far to have largely eluded analysis.

Animals↗
PubMed1995

Tracking heterochromatin.

The Second International Workshop on Drosophila Heterochromatin, held in Honolulu from January 4-7, 1995, brought together about 70 scientists from the US, Canada, Germany, Italy, Russia, and the Netherlands. After the first of these international meetings, five years ago, Mary Lou Pardue and Wolfgang Hennig, in these columns, commented on its proceedings, and on heterochromatin in general. Although the questions that they raised cannot yet be answered exhaustively, important and sometimes surprising new observations have been made, some previously tentative answers have been firmed up, and some theoretical views underwent significant shifts. We wish to reflect here a few of the data presented at the second workshop, and express some thoughts suggested to us by these recent findings.

Animals↗
PubMed1994

Molecular pathways to parallel evolution: I. Gene nexuses and their morphological correlates.

Aspects of the regulatory interactions among genes are probably as old as most genes are themselves. Correspondingly, similar predispositions to changes in such interactions must have existed for long evolutionary periods. Features of the structure and the evolution of the system of gene regulation furnish the background necessary for a molecular understanding of parallel evolution. Patently "unrelated" organs, such as the fat body of a fly and the liver of a mammal, can exhibit fractional homology, a fraction expected to become subject to quantitation. This also seems to hold for different organs in the same organism, such as wings and legs of a fly. In informational macromolecules, on the other hand, homology is indeed all or none. In the quite different case of organs, analogy is expected usually to represent attenuated homology. Many instances of putative convergence are likely to turn out to be predominantly parallel evolution, presumably including the case of the vertebrate and cephalopod eyes. Homology in morphological features reflects a similarity in networks of active genes. Similar nexuses of active genes can be established in cells of different embryological origins. Thus, parallel development can be considered a counterpart to parallel evolution. Specific macromolecular interactions leading to the regulation of the c-fos gene are given as an example of a "controller node" defined as a regulatory unit. Quantitative changes in gene control are distinguished from relational changes, and frequent parallelism in quantitative changes is noted in Drosophila enzymes. Evolutionary reversions in quantitative gene expression are also expected. The evolution of relational patterns is attributed to several distinct mechanisms, notably the shuffling of protein domains. The growth of such patterns may in part be brought about by a particular process of compensation for "controller gene diseases," a process that would spontaneously tend to lead to increased regulatory and organismal complexity. Despite the inferred increase in gene interaction complexity, whose course over evolutionary time is unknown, the number of homology groups for the functional and structural protein units designated as domains has probably remained rather constant, even as, in some of its branches, evolution moved toward "higher" organisms. In connection with this process, the question is raised of parallel evolution within the purview of activating and repressing master switches and in regard to the number of levels into which the hierarchies of genic master switches will eventually be resolved.

Animals↗
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↗