GENETIC HARM: BITTEN BY THE BODY THAT KEEPS YOU?

... We must attempt to explain, how, if ever, our existence may harm us. To address this and the other questions raised, I propose to examine what constitutes harm and whether it makes sense to say that our genetic makeup may harm us. To do this I will describe three approaches to the problem of describing the status of negative effects our genes have upon us, which I have named the "technical harm" view, the "constitutive" view, and the "harmful conditions" view. On the technical harm view, the standard definitions of harm are applied to genetic disposition in an attempt to couch genetic defects or flaws in terms of harming. The constitutive view rejects applying the concept of harm to genetic disposition on the grounds that it is impossible to separate genetic disposition from individual identity. Lastly, the harmful conditions view, which I conclude is the most successful of the three, focuses on the tendency of certain genetic dispositions to cause harm in the future and thus avoids what I will argue are the "context" shortcomings of the other two approaches. To conclude the discussion I will very briefly analyze the ramifications of a harmful conditions view for the concept of genetic disease and the prospects for genetic counseling, gene therapy, and reproductive decision making.     

COMMENTARY ON ZOHAR'S “PROSPECTS FOR‘GENETIC THERAPY’- CAN A PERSON BENEFIT FROM BEING ALTERED?”

In his paper on the effects of Prenatal Genetic Intervention (PGI) on personal identity, Noam Zohar comes to a conclusion about genetic makeup and the uses of gene therapy quite different from the one I reach in another piece in this issue. Zohar's argument rests on the contention that personal identity changes with alteration of the genome, following what I have identified as the "constitutive" view. To see that this is the pillar supporting the weight of his argument, consider the following. Questions of identity aside, how can it be that altering the genome of children suffering from Lesch-Nyhan syndrome or Tay-Sachs disease so that they now produce the enzyme that they formerly lacked does not benefit them? Clearly, if their identities were not changed, such individuals would in fact realize great benefit from PGI, since the devastating bad effects of the genetic flaw would be avoided. Such a change would certainly make the altered individuals better off, that is, it would benefit them. On this, Zohar and I do not disagree. Persistence of identity through such genetic change is the sticking point.     

THE LOCI OF EVOLUTION: HOW PREDICTABLE IS GENETIC EVOLUTION?

Is genetic evolution predictable? Evolutionary developmental biologists have argued that, at least for morphological traits, the answer is a resounding yes. Most mutations causing morphological variation are expected to reside in the cis‐regulatory, rather than the coding, regions of developmental genes. This “cis‐regulatory hypothesis” has recently come under attack. In this review, we first describe and critique the arguments that have been proposed in support of the cis‐regulatory hypothesis. We then test the empirical support for the cis‐regulatory hypothesis with a comprehensive survey of mutations responsible for phenotypic evolution in multicellular organisms. Cis‐regulatory mutations currently represent approximately 22% of 331 identified genetic changes although the number of cis‐regulatory changes published annually is rapidly increasing. Above the species level, cis‐regulatory mutations altering morphology are more common than coding changes. Also, above the species level cis‐regulatory mutations predominate for genes not involved in terminal differentiation. These patterns imply that the simple question “Do coding or cis‐regulatory mutations cause more phenotypic evolution?” hides more interesting phenomena. Evolution in different kinds of populations and over different durations may result in selection of different kinds of mutations. Predicting the genetic basis of evolution requires a comprehensive synthesis of molecular developmental biology and population genetics.     

POPULATION ON THE VERGE OF A MUTATIONAL MELTDOWN? FITNESS COSTS OF GENETIC LOAD FOR AN AMPHIBIAN IN THE WILD

Abstract.— The fitness costs of high genetic load in wild populations have rarely been assessed under natural conditions. Such costs are expected to be greatest in small, bottlenecked populations, including those occurring near range edges. Britain is at the northwesterly range limit of the natterjack toad Bufo calamita . We compared fitness attributes in two populations of this amphibian with very different recent histories. Key larval fitness attributes in B. calamita , notably growth rate and metamorph production, were substantially higher in the large outbreeding population (Ainsdale) than in the small and isolated one (Saltfleetby). These differences were manifest under seminatural conditions, when larvae were reared in mesh cages within breeding ponds at the site of the small population, and were exacerbated by high stress treatments. The results indicate that genetic load effects can be sufficiently severe enough to predispose extinction over relatively short time frames, as predicted by extinction vortex models.     

GENETIC ISOLATION BY ENVIRONMENT OR DISTANCE: WHICH PATTERN OF GENE FLOW IS MOST COMMON?

Gene flow among populations can enhance local adaptation if it introduces new genetic variants available for selection, but strong gene flow can also stall adaptation by swamping locally beneficial genes. These outcomes can depend on population size, genetic variation, and the environmental context. Gene flow patterns may align with geographic distance (IBD—isolation by distance), whereby immigration rates are inversely proportional to the distance between populations. Alternatively gene flow may follow patterns of isolation by environment (IBE), whereby gene flow rates are higher among similar environments. Finally, gene flow may be highest among dissimilar environments (counter‐gradient gene flow), the classic “gene‐swamping” scenario. Here we survey relevant studies to determine the prevalence of each pattern across environmental gradients. Of 70 studies, we found evidence of IBD in 20.0%, IBE in 37.1%, and both patterns in 37.1%. In addition, 10.0% of studies exhibited counter‐gradient gene flow. In total, 74.3% showed significant IBE patterns. This predominant IBE pattern of gene flow may have arisen directly through natural selection or reflect other adaptive and nonadaptive processes leading to nonrandom gene flow. It also precludes gene swamping as a widespread phenomenon. Implications for evolutionary processes and management under rapidly changing environments (e.g., climate change) are discussed.     

DO MALES MATTER? TESTING THE EFFECTS OF MALE GENETIC BACKGROUND ON FEMALE MEIOTIC CROSSOVER RATES IN DROSOPHILA MELANOGASTER

Meiotic recombination is a critical genetic process as well as a pivotal evolutionary force. Rates of crossing over are highly variable within and between species, due to both genetic and environmental factors. Early studies in Drosophila implicated female genetic background as a major determinant of crossover rate and recent work has highlighted male genetic background as a possible mediator as well. Our study employed classical genetics to address how female and male genetic backgrounds individually and jointly affect crossover rates. We measured rates of crossing over in a 33 cM region of the Drosophila melanogaster X chromosome using a two‐step crossing scheme exploiting visible markers. In total, we measured crossover rates of 10 inbred lines in a full diallel cross. Our experimental design facilitates measuring the contributions of female genetic background, male genetic background, and female by male genetic background interaction effects on rates of crossing over in females. Our results indicate that although female genetic background significantly affects female meiotic crossover rates in Drosophila, male genetic background and the interaction of female and male genetic backgrounds have no significant effect. These findings thus suggest that male‐mediated effects are unlikely to contribute greatly to variation in recombination rates in natural populations of Drosophila.