Biomedical subjects

Emile Zuckerkandl

Publications and source records attributed to Emile Zuckerkandl.

3 recordsLinked to original sources

PubMed2006

Combinatorial epigenetics, "junk DNA", and the evolution of complex organisms.

At certain evolutionary junctures, two or more mutations participating in the build-up of a new complex function may be required to become available simultaneously in the same individuals. How could this happen in higher organisms whose populations are small compared to those of microbes, and in which chances of combined nearly simultaneous highly specific favorable mutations are correspondingly low? The question can in principle be answered for regulatory evolution, one of the basic processes of evolutionary change. A combined resetting of transcription rates in several genes could occur in the same individual. It is proposed that, in eukaryotes, changes in epigenetic trends and epigenetically transforming encounters between alternative chromatin structures could arise frequently enough so as to render probable particular conjunctions of changed transcription rates. Such conjunctions could involve mutational changes with low specificity requirements in gene-associated regions of non-protein-coding sequences. The effects of such mutations, notably when they determine the use of histone variants and covalent modifications of histones, can be among those that migrate along chromatin. Changes in chromatin structure are often cellularly inheritable over at least a limited number of generations of cells, and of individuals when the germ line is involved. SINEs and LINEs, which have been considered "junk DNA", are among the repeat sequences that would appear liable to have teleregulatory effects on the function of a nearby promoter, through changes in their numbers and distribution. There may also be present preexisting unstably inheritable epigenetic trends leading to cellular variegation, trends endemic in a cell population based on DNA sequences previously established in the neighborhood. Either way, epigenetically conditioned teleregulatory trends may display only limited penetrance. The imposition at a distance of new chromatin structures with regulatory impact can occur in cis as well as in trans, and is examined as intrachromosomally spreading teleregulation and interchromosomal "gene kissing". The chances for two or more particular epigenetically determined regulatory trends to occur together in a cell are increased thanks to the proposed low specificity requirements for most of the pertinent sequence changes in intergenic and intronic DNA or in the distribution of middle repetitive sequences that have teleregulatory impact. Inheritable epigenetic changes ("epimutations") with effects at a distance would then perdure over the number of generations required for "assimilation" of the several regulatory novelties through the occurrence and selection, gene by gene, of specific classical mutations. These mutations would have effects similar to the epigenetic effects, yet would provide stability and penetrance. The described epigenetic/genetic partnership may well at times have opened the way toward certain complex new functions. Thus, the presence of "junk DNA", through co-determining the (higher or lower) order and the variants of chromatin structure with regulatory effects at a distance, might make an important contribution to the evolution of complex organisms.

Animals↗

PubMed2006

Intelligent design and biological complexity.

Before any intelligence can appear, a world endowed with the potential for being experienced as a body of phenomena has to be existent. Indeed, if there is to be an intelligence, there first has to be something intelligible. Hence, when an intelligence is present, "creation" must already have taken place. Nevertheless, biological complexity has been deemed by some to be one of the privileged points of insertion of a supernatural intelligence endowed with temporal and causal primacy. In the course of a critical review, it is pointed out that the spectacle of nature's spontaneous tinkering with the structures and performances of informational macromolecules and with interactive connections among these molecules suggests that intelligence and design are absent from evolution. Nor is intelligent design required for explaining biological complexity, which can increase spontaneously as a byproduct of combinatorial intermolecular gambles and of the restoration of molecular damage wrought by mutations. One of the possible molecular pathways to spontaneous evolutionary increases in complexity is described.

Biological Evolution↗

PubMed2002

Why so many noncoding nucleotides? The eukaryote genome as an epigenetic machine.

It is recalled that dispensability of sequences and neutral substitution rate must not be construed to be markers of nonfunctionality. Different aspects of functionality relate to differently-sized nucleotide communities. At the time cells became nucleated, a boom of epigenetic processes led to uses of DNA that required many more nucleotides operating collectively than do functions definable in terms of classical genetics. Each order of magnitude of nucleotide plurality was colonized by functions germane to that order. The eukaryote genome became a great epigenetic machine. Sequences of different levels of nucleotide plurality are briefly discussed from the point of view of their functional relevance. By their activities as both transcribed genes and cis-acting repeats, SINEs and LINEs are the principal link between genetic and epigenetic processes. SINEs can act as local repeats to produce position effect variegation (PEV) in a nearby gene. PEV may thus represent a general method of overall transcriptional regulation at the level of cell collectivities. When tracking the scale dependence of nucleotide function, one finds the 100 kb order of nucleotide plurality to provide epigenetically the basis at once for PEV, imprinting, and cell determination, with sectorial repressibility a trait common to the three. In sectorial repressibility, introns may play a structural role favoring the stability of higher-order chromatin structures. At that level of nucleotide involvement, nonconserved nonhomologous nonprotein-coding sequences may often play the same structural roles. In addition, genomic distance per se--and, therefore, the mass of intervening nucleotides--can have functional effects. Distances between enhancers and promoters need to be probed in this respect. At the 1,000 kb level of nucleotide function, attention is focused on the formation of centromeres. It is one of the levels of nucleotide plurality per function where specificity in the generation of DNA/protein complexes seems to depend more upon the structural fit among factors than upon the DNA sequence. This circumstance may explain in part the prevailing difficulty in recognizing the functional nature of sequences among non-protein-coding nucleotide arrays and the propensity among investigators to tag the majority of DNA sequences in higher organisms as functionally meaningless. Noncoding DNA often may not be 'selected' as an appropriate niche for a certain function, but be 'elected' in that capacity by a group of factors, as a preexisting sequence that is only now called upon to serve. Much of the non-protein-coding DNA may thus be only conditionally functional and in fact may never be elected to functions at a high level of nucleotide plurality. Eukaryotes are composites, at different levels of this plurality, of the functional and the nonfunctional, as well as of the conditionally functional and the outright functional. Thus, a sequence that is nonfunctional at one level of nucleotide plurality may participate in a functional sequence at a more inclusive level. In the end, every nucleotide is at least infinitesimally functional if, for metabolic and developmental reasons, the chromatin mass as such becomes a selectable entity. Given the scale dependence of nucleotide function, large amounts of 'junk DNA', contrary to common belief, must be assumed to contribute to the complexity of gene interaction systems and of organisms.

DNA, Intergenic↗