Heterochromatin

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H e t eroa l l e l e

The interpretation they cautiously presented was that the proteinaceous phage coat remained outside the cell, while the DNA was injected into the cell. This result was immediately taken as confirmation that the DNA was the substance which was associated with the genetic continuity of the phage and that the protein coat was merely a transport vehicle. This experiment is usually described in idealized terms, although the actual data presented by Hershey and Chase certainly allowed for some possible protein to accompany the DNA into the cell. In the 1960s Hershey turned his attention to the lysogenic phage lambda and devised simple yet elegant approaches to study the physical states of the lambda DNA. He pioneered methods for dealing with large DNA molecules, which are highly sensitive to breakage by shear forces in solutions. His methods for DNA extraction (phenol) and zone sedimentation (in sucrose gradients) allowed him to show that lambda DNA existed in both linear and circular forms, and that it has unpaired (presumably complementary) cohesive termini. This work was seminal in developing our current understanding of lysogeny as well as in the applications of lambda bacteriophage in recombinant DNA technologies. See also: Bacteriophages; DelbruÈck, Max; Luria, Salvador

Heteroallele F W Stahl Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0604

Heteroalleles are alternative mutant forms of a given gene resident at the same locus.

Heteroallelic Complementation A heteroallelic diploid is characteristically mutant in phenotype. A heteroallelic diploid that has wild-type or quasi wild-type phenotype is said to manifest interallelic (or intragenic) complementation. Such complementation often reflects either a multimeric state of the functional protein product of that gene or two or more domains within the protein manifesting more or less independent functions.

Heteroallelic Recombination When the altered nucleotide sequences defining the two heteroalleles are not overlapping, interallelic

(intragenic) recombination can generate the wild-type as well as the doubly mutant allele. When genes are small (intron-free), recombination between heteroalleles usually occurs by gene conversion.

History In the 1940s and 1950s, demonstrations of interallelic complementation and recombination strained the classical definition of a gene. Complementation between mutations is a classical demonstration that two mutations are in separate genes, defined as units of function. However, understanding of quarternary protein structure soon rationalized the exceptional cases of heteroallelic complementation. Recombination between mutants is a classical demonstration that the two mutations are in separate genes, defined as units of recombination. However, analysis of the rll gene of bacteriophage T4 combined with the Watson± Crick hypothesis for DNA structure established the modern view that a gene is a segment of a continuous DNA duplex with recombination possible between any pair of adjacent nucleotides (Benzer, 1955).

Reference

Benzer S (1955) Fine structure of a genetic region in bacteriophage. Proceedings of the National Academy of Sciences, USA 41: 344±354.

See also: Complementation Test; Gene Conversion

Heterochromatin A T Sumner Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0605

Heterochromatin was originally defined by Heitz in 1928 as chromosome segments that failed to decondense at the end of telophase, but which remained condensed throughout interphase, and which appeared as condensed segments at the following prophase, that is, it showed positive heteropyknosis. Subsequently, it was realized that there is more than one class of heterochromatin. `Constitutive heterochromatin' is found at virtually all stages of an organism's life cycle, in the same place on both of a pair of homologs, can be stained by specific methods, and generally contains distinctive types of DNA. `Facultative heterochromatin,' on the other hand, only occurs in one of a pair of homologs, cannot generally be stained distinctively, and necessarily contains the same type of DNA as that found in the nonheterochromatic homolog. The best-known

Heterochronic Mutation 927 example of the latter is the inactive X chromosome of female mammals.

Constitutive Heterochromatin Constitutive heterochromatin is most easily demonstrated using C-banding; a variety of other chromosome banding methods produce specific staining of certain heterochromatic regions of chromosomes in certain species. Characteristically, constitutive heterochromatin consists largely of highly repetitive (`satellite') DNA, although blocks of heterochromatin may not necessarily consist exclusively of such DNA, and in some species moderately repetitive rather than highly repetitive DNA seems to be present. The DNA of constitutive heterochromatin is late-replicating, and in mammals, its cytosines are often methylated. A number of proteins have been described that are either specific to, or concentrated in, constitutive heterochromatin; such proteins may well be involved in the condensed state of heterochromatin. Heterochromatin has generally been regarded as genetically inert. The quantity in the genome can vary extensively without any apparent phenotypic effects. In Drosophila it is not replicated during polytenization of chromosomes, and in certain other organisms heterochromatin is eliminated in somatic cells, and retained only in the germline. The highly repetitive DNA sequences found in most heterochromatin could not be translated into proteins. Nevertheless, constitutive heterochromatin is not without effects. It can have profound effects on the position and number of chiasmata at meiosis; induce the inactivation of genes close to it (position-effect variegation); and in Drosophila can contain Y-chromosome fertility factors, factors involved in pairing and disjunction of achiasmate chromosomes, and certain other unconventional genetic factors such as Responder and ABO. The genetics of few organisms have been studied as intensively as that of Drosophila, and it may yet turn out that constitutive heterochromatin in many species contains nonconventional factors.

Facultative Heterochromatin The best-known example of facultative heterochromatin is the inactive X chromosome of female mammals, in which one of the X chromosomes is permanently inactivated early in development, apparently as a means of dosage compensation, so that the amount of X-chromosome gene products produced is similar in males (with only one X) and in females (with two X chromosomes). (It should be noted that in birds, with an independently evolved ZW/ZZ sex chromosome system, there appears to be no dosage compensation, and no facultative heterochromatin,

while in Drosophila dosage compensation is achieved by increased transcription from the single X chromosome in males.) Like constitutive heterochromatin, the facultative heterochromatin of the mammalian inactive X is late-replicating, and its DNA is more methylated than that of its euchromatic homolog; however, the inactive X cannot be stained distinctively by chromosome banding techniques. The other reasonably well-known system of facultative heterochromatin occurs in the mealybugs. In the males of this insect, the entire paternal set of chromosomes becomes heterochromatinized, although this does not appear to be related to sex determination. In somatic cells, the heterochromatin replicates less than the euchromatin, while in male meiosis, two wholly heterochromatic and two wholly euchromatic nuclei form, of which only the two latter develop into spermatozoa.

Heterochromatin: Substance or State? In the past, it was argued whether heterochromatin was a substance or a state. We can now answer that question. Constitutive heterochromatin is evidently a substance, since it consists of specific DNA fractions combined with specific proteins. Conversely, facultative heterochromatin is evidently a state, as its DNA sequence is identical to that of its euchromatic homolog, and in rare cases its heterochromatinization is reversible. Euchromatin inactivated as a result of position-effect variegation, when the inactivation spreads from an adjacent region of constitutive heterochromatin, is clearly also a state of chromatin. Nevertheless, there are occasional systems in which typical constitutive heterochromatin becomes decondensed, for example in the early stages of development in Drosophila, when the rate of division is very high, and there may perhaps be no time to condense the heterochromatin. In spite of these exceptions, it is still useful to make the distinction between constitutive and facultative heterochromatin. See also: Chromosome Banding; Heteropyknosis; Position Effects; X-Chromosome Inactivation

Heterochronic Mutation A E Rougvie Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0606

The term heterochronic is derived from the Greek heteros, meaning other or different, and khronos,