Desmond W. Cooper

Genetics of hypertension in pregnancy: possible single gene control of pre‐eclampsia and eclampsia in the descendants of eclamptic women

Summary. Our report concerns the incidences of pre‐eclampsia and eclampsia in 147 sisters, 248 daughters, 74 granddaughters, and 131 daughters‐in‐law of women who have had eclampsia. The disorder is highly heritable. We have analysed the data in two ways, firstly, as a single gene condition and, secondly, as a multifactorial condition. The observed incidences fit closely with the single gene model with frequency of the putative gene being 0.25. When Falconers method of estimating heritabilities of discrete characters is used, estimates of 120% (sisters), 88% (daughters), and 105% (granddaughters)—none significantly different from 100%—are obtained. Insofar as possible, our definition of pre‐eclampsia corresponds with EPH in the descriptive classification of the Organisation Gestosis and to ‘severe pre‐eclampsia’ in Nelsons classification. The women were delivered in many different hospitals, however, and many records fail to provide all of the essential information

Genetic control of susceptibility to eclampsia and miscarriage

Summary. An analysis has been made of 48 pedigrees selected (ascertained) through an affected mother in the first generation. These pedigrees mainly involve cases of eclampsia which occurred before its recent decline in incidence. The data confirm the genetic determination of susceptibility indicated by published data on eclampsia/preeclampsia. There is a suggestion that the fetal genotype can contribute to susceptibility to eclampsia in its mother, in contrast to previous findings that susceptibility to pre‐eclampsia is controlled solely by the maternal genotype. An association between eclampsia and miscarriage is shown in the data. We argue that this suggests that the primary mode of action of the gene(s) involved is to affect the interaction between uterine and placental tissue.

GENETICS OF PRE-ECLAMPSIA

Pre-eclampsia is a serious complication of the second half of human pregnancy which occurs at frequencies of 1 % to 5% in most parts of the world. It is characterized clinically by high blood pressure, proteinuria, and generalized edema in association with a wide range of pathophysiological organ and system disturbances. Untreated, it can lead to the occurrence of epileptic-like grand-mal convulsions (eclampsia), which is a source of considerable maternal and fetal morbidity. The disease is unusual in having no known cause, although an immunological impairment is suspected. Here we review the evidence that the condition is genetic in origin. Several genetic models are discussed. Markedly raised incidences are seen in blood relatives (mothers, daughters, sisters, and granddaughters) but not in relatives by marriage (daughters-in-law, mothers-in-law). This suggests that the condition is caused by maternal genes. Other evidence, however, implicates the fetal genotype. The most decisive data supporting this s...

Genetic analysis of a documented population bottleneck: introduced Bennett’s wallabies (Macropus rufogriseus rufogriseus) in New Zealand

Few bottlenecks of wild populations are sufficiently well‐documented to constitute models for testing theories about the impact of bottlenecks on genetic variation, and subsequent population persistence. Relevant details of the Bennett’s wallaby (Macropus rufogriseus rufogriseus) introduction into New Zealand were recorded (founder number, source and approximate bottleneck duration) and suggest this may provide a rare opportunity to examine the efficacy of tests designed to detect recent bottlenecks in wild populations. We first assessed the accuracy of historic accounts of the introduction using genetic diversity detected in mitochondrial DNA (mtDNA) and at five microsatellite loci. Phylogenetic analyses of mtDNA D‐loop sequence haplotypes were consistent with the reported origin of the founders as Tasmania, rather than one of the Bass Strait islands in which Bennett’s wallabies are also found. Microsatellite allele frequencies from the Tasmanian source population were then used to seed bottleneck simulations encompassing varying sizes and numbers of generations, in order to assess the severity of bottleneck consistent with diversity observed in the New Zealand population. The results suggested that the founder number was unlikely to have been as small as the three animals suggested by the account of the introduction. Nonetheless, the bottleneck was probably severe; in the range of three to five pairs of wallabies for one to three generations. It resulted in significantly reduced levels of allelic diversity and heterozygosity relative to the source population. This bottleneck is only detectable under the infinite allele model (IAM) and not under the stepwise mutation model (SMM) or the two‐phase model (TPM), and possible explanations for this are discussed.

Detecting bottlenecks using BOTTLENECK 1.2.02 in wild populations: the importance of the microsatellite structure

Reduced, or bottlenecked, populations are more prone to adverse events. Thus, the detection of genetic bottleneck signatures in wildlife is an important issue for conservation. BOTTLENECK 1.2.02 is a software commonly used for detecting genetic characteristics of past bottlenecks. Here we test the efficiency with which this software detects bottlenecks in two koala populations of known history. The sign test performed well for both populations, particularly under the infinite alleles model for mutation. This suggests this model could be the more realistic for marsupial microsatellites than other mutation models. Under the allele frequency distribution test, the two populations falsely appeared to be at mutation/drift equilibrium. However, this test could detect the bottleneck when only imperfect repeat microsatellites were included in the analysis. We thus recommend further investigation of imperfect repeat microsatellites, which could be more powerful for bottleneck detection. These results underline the cautious approach researchers and conservationists should take when studying the past of unknown populations.

Landscape discontinuities influence gene flow and genetic structure in a large, vagile Australian mammal, Macropus fuliginosus

Large vagile mammals typically exhibit little genetic structuring across their range, particularly when their habitat is essentially continuous. We investigated the population genetic structure of a large vagile Australian macropodid, Macropus fuliginosus, which is continuously distributed across most of southern Australia, using nine highly polymorphic nuclear microsatellite loci. Five distinct genetic units were identified across the range, four on the mainland and one on Kangaroo Island. In addition to the predicted historic Nullarbor Plain Barrier, two unexpected mainland barriers to gene flow were identified. Both were associated with landscape discontinuities (Swan River, Flinders Ranges), which appear within the dispersal capabilities of M. fuliginosus. Typical of large vagile mammals, M. fuliginosus displays high genetic diversity (with the exception of an insular population) and weak genetic structuring (within genetic units). However, the expansion of M. fuliginosus from southwestern Australia during the Pleistocene has resulted in significantly reduced genetic diversity in eastern populations. No significant sex‐biased dispersal was detected, although differences in habitat, densities and climatic conditions between the eastern and western regions of the range appear to influence dispersal with the effects of isolation by distance only evident in the west. These results suggest that the biogeography of southern Australia is more complex than previously thought and reveal that seemingly minor landscape features can significantly impact genetic structuring in large vagile mammals.

Immunocontraception of mammalian wildlife: ecological and immunogenetic issues

Immunocontraception involves stimulating immune responses against gametes or reproductive hormones thus preventing conception. The method is being developed for the humane control of pest and overabundant populations of mammalian wildlife. This paper examines three fundamental issues associated with its use: (1) the difficulties of obtaining responses to self-antigens, (2) the likely evolution of genetically based non-response to immunocontraceptive agents, and (3) the possible changes in the array of pathogens possessed by the target species after generations of immunocontraception. Our review of the literature demonstrates that the barriers to an effective immunocontraceptive are at present very basic. Should they be overcome, the effects of immunocontraception on the immunogenetic constitution of wildlife populations through the selection for non-responders must be examined. We suggest that the attempt to use the animals own immune system to modulate reproduction may be incompatible with the basic biological function of protection against infectious disease. Research programs on mammalian immunocontraception should involve measurement of the heritability of non-response and an assessment of the likely change in the response of the contracepted population to possible pathogens.

Intraspecific variation, sex-biased dispersal and phylogeography of the eastern grey kangaroo (Macropus giganteus)

Genetic information has played an important role in the development of management units by focusing attention on the evolutionary properties and genetics of populations. Wildlife authorities cannot hope to manage species effectively without knowledge of geographical boundaries and demic structure. The present investigation provides an analysis of mitochondiral DNA and microsatellite data, which is used to infer both historical and contemporary patterns of population structuring and dispersal in the eastern grey kangaroo (Macropus giganteus) in Australia. The average level of genetic variation across sample locations was one of the highest observed for marsupials (h=0.95, HE=0.82). Contrary to ecological studies, both genic and genotypic analyses reveal weak genetic structure of populations, where high levels of dispersal may be inferred up to 230 km. The movement of individuals was predominantly male-biased (average Nem=22.61, average Nfm=2.73). However, neither sex showed significant isolation by distance. On a continental scale, there was strong genetic differentiation and phylogeographic distinction between southern (TAS, VIC and NSW) and northern (QLD) populations, indicating a current and/or historical restriction of gene flow. In addition, it is evident that northern populations are historically more recent, and were derived from a small number of southern founders. Phylogenetic comparisons between M. g. giganteus and M. g. tasmaniensis indicated that the current taxonomic status of these subspecies should be revised as there was a lack of genetic differentiation between the populations sampled.

Effects of a Gonadotropin-Releasing Hormone Agonist Implant on Reproduction in a Male Marsupial, Macropus eugenii

Abstract This study evaluated the potential of slow-release GnRH agonist (deslorelin) implants to inhibit reproductive function in the male tammar wallaby. The specific aim was to measure the effects of graded dosages of deslorelin on testes size and plasma LH and testosterone concentrations. Adult male tammar wallabies were assigned to four groups (n = 6 per group) and received the following treatment: control, placebo implant; low dose, 5 mg deslorelin; medium dose, 10 mg; high dose, 20 mg. All dosages of deslorelin induced acute increases (P < 0.001) in plasma LH and testosterone concentrations within 2 h, with concentrations remaining elevated during the first 24 h but returning to pretreatment levels by Day 7. Thereafter, there was no evidence of a treatment-induced decline in plasma testosterone concentrations. There was no detectable difference in basal LH concentrations between treated and control animals, nor was there a significant change in testes width or length (P > 0.05). These results suggest that the male tammar wallaby is resistant to the contraceptive effects of chronic GnRH agonist treatment. Despite the maintenance of testosterone secretion, the majority of male tammars (10 of 17) failed to respond to a GnRH challenge with a release of LH between Days 186 and 197 of treatment. The failure of animals to respond to exogenous GnRH suggests a direct effect of deslorelin on the pituitary, resulting in a level of desensitization that was sufficient to inhibit a LH surge but insufficient to inhibit basal LH secretion. The variation between animals is believed to result from earlier recovery of some individuals, in particular those that received a lower dose, or individual resistance to the desensitization process.

Immunoglobulin G levels in fetal and newborn tammar wallabies (Macropus eugenii).

Immunoglobulin G (IgG) was measured in fetal, neonatal and colostral samples from the tammar wallaby (Macropus eugenii) in order to study the possibility of passively acquired immunity. Samples were obtained from young at a known stage of gestation and at known times (to the minute) after birth. IgG was present (in increasing levels of concentration) in fetal serum, neonatal serum and colostrum. Since the fetus and neonate are probably unable to make immunoglobulin (Ig), it is hypothesized that transplacental and trans-gut transmission takes place from mother to offspring. The vascular yolk sac placenta has a high concentration of IgG, and is the most likely route of transmission from mother to young. Some observations were made of IgA which was found only in colostrum. No Ig of either kind was found in yolk sac fluid.