Molecular genetics of sudden cardiac death in small animals - A review

Sudden cardiac death in small animals is uncommon but often occurs due to cardiac conduction defects or myocardial diseases. Primary cardiac conduction defects are mainly caused by mutations in genes involved in impulse conduction processes (e.g., gapjunction genes and transcription factors) or repolarisation processes (e.g., ion-channel genes), whereas primary cardiomyopathies are mainly caused by defective force generation or force transmission due to gene mutations in either sarcomeric or cytoskeleton proteins. Although over 50 genes have been identified in humans directly or indirectly related to sudden cardiac death, no genetic aetiologies have been identified in small animals. Sudden cardiac deaths have been also reported in German Shepherds and Boxers. A better understanding of molecular genetic aetiologies for sudden cardiac death will be required for future study toward unveiling actiology in sudden cardiac death in small animals. (c) 2005 Elsevier Ltd. All rights reserved.

Restricted mating dispersal and strong breeding group structure in a mid-sized marsupial mammal (Petrogale penicillata)

Ecological genetic studies have demonstrated that spatial patterns of mating dispersal, the dispersal of gametes through mating behaviour, can facilitate inbreeding avoidance and strongly influence the structure of populations, particularly in highly philopatric species. Elements of breeding group dynamics, such as strong structuring and sex-biased dispersal among groups, can also minimize inbreeding and positively influence levels of genetic diversity within populations. Rock-wallabies are highly philopatric mid-sized mammals whose strong dependence on rocky terrain has resulted in series of discreet, small colonies in the landscape. Populations show no signs of inbreeding and maintain high levels of genetic diversity despite strong patterns of limited gene flow within and among colonies. We used this species to investigate the importance of mating dispersal and breeding group structure to inbreeding avoidance within a 'small' population. We examined the spatial patterns of mating dispersal, the extent of kinship within breeding groups, and the degree of relatedness among brush-tailed rock-wallaby breeding pairs within a colony in southeast Queensland. Parentage data revealed remarkably restricted mating dispersal and strong breeding group structuring for a mid-sized mammal. Breeding groups showed significant levels of female kinship with evidence of male dispersal among groups. We found no evidence for inbreeding avoidance through mate choice; however, anecdotal data suggest the importance of life history traits to inbreeding avoidance between first-degree relatives. We suggest that the restricted pattern of mating dispersal and strong breeding group structuring facilitates inbreeding avoidance within colonies. These results provide insight into the population structure and maintenance of genetic diversity within colonies of the threatened brush-tailed rock-wallaby.

Significant patterns of population genetic structure and limited gene flow in a threatened macropodid marsupial despite continuous habitat in southeast Queensland, Australia

Many endangered species worldwide are found in remnant populations, often within fragmented landscapes. However, when possible, an understanding of the natural extent of population structure and dispersal behaviour of threatened species would assist in their conservation and management. The brush-tailed rock-wallaby (Petrogale penicillata), a once abundant and widespread rock-wallaby species across southeastern Australia, has become nearly extinct across much of the southern part of its range. However, the northern part of the species' range still sustains many small colonies closely distributed across suitable habitat, providing a rare opportunity to investigate the natural population dynamics of a listed threatened species. We used 12 microsatellite markers to investigate genetic diversity, population structure and gene flow among brush-tailed rock-wallaby colonies within and among two valley regions with continuous habitat in southeast Queensland. We documented high and signifcant levels of population genetic structure between rock-wallaby colonies embedded in continuous escarpment habitat and forest. We found a strong and significant pattern of isolation-by-distance among colonies indicating restricted gene flow over a small geographic scale (< 10 km) and conclude that gene flow is more likely limited by intrinsic factors rather than environmental factors. In addition, we provide evidence that genetic diversity was significantly lower in colonies located in a more isolated valley region compared to colonies located in a valley region surrounded by continuous habitat. These findings shed light on the processes that have resulted in the endangered status of rock-wallaby species in Australia and they have strong implications for the conservation and management of both the remaining 'connected' brush-tailed rock-wallaby colonies in the northern parts of the species' range and the remnant endangered populations in the south.

Studying phenotypic evolution using multivariate quantitative genetics

Quantitative genetics provides a powerful framework for studying phenotypic evolution and the evolution of adaptive genetic variation. Central to the approach is G, the matrix of additive genetic variances and covariances. G summarizes the genetic basis of the traits and can be used to predict the phenotypic response to multivariate selection or to drift. Recent analytical and computational advances have improved both the power and the accessibility of the necessary multivariate statistics. It is now possible to study the relationships between G and other evolutionary parameters, such as those describing the mutational input, the shape and orientation of the adaptive landscape, and the phenotypic divergence among populations. At the same time, we are moving towards a greater understanding of how the genetic variation summarized by G evolves. Computer simulations of the evolution of G, innovations in matrix comparison methods, and rapid development of powerful molecular genetic tools have all opened the way for dissecting the interaction between allelic variation and evolutionary process. Here I discuss some current uses of G, problems with the application of these approaches, and identify avenues for future research.

Transmission ratio distortion in the human body louse, Pediculus humanus (Insecta : Phthiraptera)

We studied inheritance at three microsatellite loci in eight F-1 and two F-2 families of the body (clothes) louse of humans, Pediculus humanus. The alleles of heterozygous female-parents were always inherited in a Mendelian fashion in these families. Alleles from heterozygous male-parents, however, were inherited in two different ways: (i) in a Mendelian fashion and (ii) in a non-Mendelian fashion, where males passed to their offspring only one of their two alleles, that is, 100% nonrandom transmission. In male body lice, where there was non-Mendelian inheritance, the paternally inherited set of alleles was eliminated. We interpret this pattern of inheritance as evidence for extreme transmission ratio distortion of paternal alleles in this species.

Non-major-histocompatibility-complex genetics of ankylosing spondylitis

There is strong evidence from twin and family studies indicating that a substantial proportion of the heritability of susceptibility to ankylosing spondylitis (AS) and its clinical manifestations is encoded by non-major-histocompatibility-complex genes. Efforts to identify these genes have included genomewide linkage studies and candidate gene association studies. One region, the interleukin (IL)-I gene complex on chromosome 2, has been repeatedly associated with AS in both Caucasians and Asians. It is likely that more than one gene in this complex is involved in AS, with the strongest evidence to date implicating IL-IA. Identifying the genes underlying other linkage regions has been difficult due to the lack of obvious candidates and the low power of most studies to date to identify genes of the small to moderate magnitude that are likely to be involved. The field is moving towards genomewide association analysis, involving much larger datasets of unrelated cases and controls. Early successes using this approach in other diseases indicates that it is likely to identify genes in common diseases like AS, but there remains the risk that the common-variant, common-disease hypothesis will not hold true in AS. Nonetheless, it is appropriate for the field to be cautiously optimistic that the next few years will bring great advances in our understanding of the genetics of this condition.

Genetic structure and male-mediated gene flow in the ghost bat (Macroderma gigas)

The Australian ghost bat is a large, opportunistic carnivorous species that has undergone a marked range contraction toward more mesic, tropical sites over the past century. Comparison of mitochondrial DNA (mtDNA) control region sequences and six nuclear microsatellite loci in 217 ghost bats from nine populations across subtropical and tropical Australia revealed strong population subdivision (mtDNA phi(ST) = 0.80; microsatellites URST = 0.337). Low-latitude (tropical) populations had higher heterozygosity and less marked phylogeographic structure and lower subdivision among sites within regions (within Northern Territory [NT] and within North Queensland [NQ]) than did populations at higher latitudes (subtropical sites; central Queensland [CQ]), although sampling of geographically proximal breeding sites is unavoidably restricted for the latter. Gene flow among populations within each of the northern regions appears to be male biased in that the difference in population subdivision for mtDNA and microsatellites (NT phi(ST) = 0.39, URST = 0.02; NQ phi(ST) = 0.60, URST = -0.03) is greater than expected from differences in the effective population size of haploid versus diploid loci. The high level of population subdivision across the range of the ghost bat contrasts with evidence for high gene flow in other chiropteran species and may be due to narrow physiological tolerances and consequent limited availability of roosts for ghost bats, particularly across the subtropical and relatively arid regions. This observation is consistent with the hypothesis that the contraction of the species' range is associated with late Holocene climate change. The extreme isolation among higher-latitude populations may predispose them to additional local extinctions if the processes responsible for the range contraction continue to operate.

Teaching principles of genetics through SNP analysis

An understanding of inheritance requires comprehension of genetic processes at all levels, from molecules to populations. Frequently genetics courses are separated into molecular and organismal genetics and students may fail to see the relationships between them. This is particularly true with human genetics, because of the difficulties in designing experimental approaches which are consistent with ethical restrictions, student abilities and background knowledge, and available time and materials. During 2005 we used analysis of single nucleotide polymorphisms (SNPs) in two genetic regions to enhance student learning and provide a practical experience in human genetics. Students scanned databases to discover SNPs in a gene of interest, used software to design PCR primers and a restriction enzyme based assay for the alleles, and carried out an analysis of the SNP on anonymous individual and family DNAs. The project occupied eight to ten hours per week for one semester, with some time spent in the laboratory and some spent in database searching, reading and writing the report. In completing their projects, students acquired a knowledge of Mendel’s first law (through looking at inheritance patterns), Mendel’s second law and the exceptions (the concepts of linkage and linkage disequilibrium), DNA structure (primer design and restriction enzyme analysis) and function (SNPs in coding and non-coding regions), population genetics and the statistical analysis of allele frequencies, genomics, bioinformatics and the ethical issues associated with the use of human samples. They also developed skills in presentation of results by publication and conference participation. Deficiencies in their understanding (for example of inheritance patterns, gene structure, statistical approaches and report writing) were detected and guidance given during the project. SNP analysis was found to be a powerful approach to enhance and integrate student understanding of genetic concepts.