David G. King

Simple sequence repeats as a source of quantitative genetic variation

Most traits in biological populations appear to be under stabilizing selection, which acts to eliminate quantitative genetic variation. Yet, virtually all measured traits in biological populations continue to show significant quantitative genetic variation. The paradox can be resolved by postulating the existence of an abundant, though unspecified, source of mutations that has quantitative effects on phenotype, but does not reduce fitness. Does such a source actually exist? We propose that it does, in the form of repeat-number variation in SSRs (simple sequence repeats, of which the triplet repeats of human neurodegenerative diseases are a special case). Viewing SSRs as a major source of quantitative mutation has broad implications for understanding molecular processes of evolutionary adaptation, including the evolutionary control of the mutation process itself.

Evolutionary tuning knobs

Abstract Spontaneous mutations are the ultimate source of all natural genetic variation upon which evolution depends. Recent observations have revealed that many genes are associated with mutation-prone DNA tracts, each consisting of a simple motif repeated over and over in tandem. These simple sequence repeats (SSRs) may provide a previously unrecognized source of abundant quantitative genetic variation based on mutations that are frequent, site-specific and reversible, yet seldom substantially deleterious. Such sequences may be evolutionarily significant, equipping genomes and individual genes with adjustable ‘tuning knobs’ for efficient adaptation.

The Drosophila Giant Fiber System

Normal functioning of the nervous system depends on the formation of vast numbers of specific connections between neurons. During development, each of the thousands, millions, or billions of cells in a nervous system connects with a specific set of target cells. We currently have no knowledge of the molecular basis of this specificity. The long-term goal of our work is to identify genes that are directly involved in neural connectivity and then to use this knowledge to identify the gene products necessary for proper connectivity. It will be a major advance in neuroscience if the class (or classes) of molecules involved in nerve-cell recognition and connection can be identified.

Variation and Fidelity: The Evolution of Simple Sequence Repeats as Functional Elements in Adjustable Genes

The functional properties of simple sequence repeats (SSRs) support an expanded understanding of evolution’s effect on mutability. These DNA tracts are characterized by high rates of gain or loss in the number of tandem repetitions of a short DNA motif. Such mutations are remarkable for being frequent, site-specific and readily reversible. Furthermore, many SSRs are functionally integrated into the genome, so that such changes in tract length can exert a quantitative regulatory effect on gene transcription activity. Although the characteristic mutability of SSRs increases the site-specific rate of mutation, the quantitative effect minimizes the probability of significantly deleterious outcome. Such mutable sites can thus create a favorable balance between the costs and the benefits of mutability.

A Simple Device to Help Re-Embed Thick Plastic Sections

The removal of epoxy capsules cast on glass slides is facilitated by 1) partial polymerization and brief exposure to elevated temperature, and 2) use of a slide holder to support the hot slides and reduce the chance of breakage. With this procedure, plastic sections routinely dried onto glass slides are available for re-embedding and subsequent thin sectioning.

Indirect selection of implicit mutation protocols

A hypothesis that mutability evolves to facilitate evolutionary adaptation is dismissed by many biologists. Their skepticism is based on a theoretical expectation that natural selection must minimize mutation rates. That view, in turn, is historically grounded in an intuitive presumption that “the vast majority of mutations are harmful.” But such skepticism is surely misplaced. Several highly mutagenic genomic patterns, including simple sequence repeats, and transposable elements, are integrated into an unexpectedly large proportion of functional genetic loci. Because alleles arising within such patterns can retain an intrinsic propensity toward a particular style of mutation, natural selection that favors any such allele can indirectly favor the sites mutability as well. By exploiting patterns that have produced beneficial alleles in the past, indirect selection can encourage mutation within constraints that reduce the probability of deleterious effect, thereby shaping implicit “mutation protocols” that effectively promote evolvability.

Heretical DNA Sequences

When “Genomic clues to DNA treasure sometimes lead nowhere” (D. Monroe, News Focus, 10 July, p. [142][1]), the apparent impasse should indeed stimulate more subtle interpretation. Exceptions to the “conservation equals function” rule for sequence evolution are “heretical” only when

Has Simple Sequence Repeat Mutability Been Selected to Facilitate Evolution

While adaptation and speciation begin with heritable variation, the underlying processes of mutation remain poorly understood. One particularly interesting source for prolific and adaptively meaningful variation is presented by the exceptionally high mutability of simple sequence repeats (SSRs: microsatellites and minisatellites). Frequent mutations at SSR sites alter the number of tandem repeats and create extensive polymorphism. Although most SSR variants are commonly presumed to be neutral, SSR variation has been shown to influence many biochemical, morphological, physiological, and behavioral characters, with at least a few examples offering evidence of response to selection. The type and degree of phenotypic variation depend upon each SSRs motif and on its location in exon, intron, or regulatory region, but the generation of abundant repeat-number variation is intrinsic to all of these repetitive sequences. Given the widespread distribution of SSRs within most genomes and their potential to modify a...

Evolutionary loss of a neural pathway from the nervous system of a fly (Glossina morsitans/Diptera)

Three pairs of specialized axons found in other muscoid flies are absent in the tsetse, Glossina morsitans, which also lacks the tergotrochanteral muscle. Neither light nor electron microscopy could demonstrate any evidence for the cervical giant fiber axon, the peripherally synapsing axon, or the tergotrochanteral motor axon. The specialized characteristics of these axons must have been altered during the evolution of Glossina. This divergence of individual neurons from the more typical muscoid pattern not only demonstrates the evolutionary modification of specific identified cells; it may also provide an opportunity to study the ontogenetic determination of unique neuronal features.