This study reports the identification and characterization of markers of Alzheimer's disease (AD) in aged sheep (Ovis aries) as a preliminary step toward making a genetically modified large animal model of AD. Importantly, the sequences of key proteins involved in AD pathogenesis are highly conserved between sheep and human. The processing of the amyloid-β (Aβ) protein is conserved between sheep and human, and sheep Aβ/Aβ ratios in cerebrospinal fluid (CSF) are also very similar to human. In addition, total tau and neurofilament light levels in CSF are comparable with those found in human. The presence of neurofibrillary tangles in aged sheep brain has previously been established; here, we report for the first time that plaques, the other pathologic hallmark of AD, are also present in the aged sheep brain. In summary, the biological machinery to generate the key neuropathologic features of AD is conserved between the human and sheep, making the sheep a good candidate for future genetic manipulation to accelerate the condition for use in pathophysiological discovery and therapeutic testing.

Alzheimer’s disease (AD) is one of the looming health crises of the near future. Increasing lifespans and better medical treatment for other conditions mean that the prevalence of this disease is expected to triple by 2050. The impact of AD includes both the large toll on individuals and their families as well as a large financial cost to society. So far, we have no way to prevent, slow, or cure the disease. Current medications can only alleviate some of the symptoms temporarily. Many animal models of AD have been created, with the first transgenic mouse model in 1995. Mouse models have been beset by challenges, and no mouse model fully captures the symptomatology of AD without multiple genetic mutations and/or transgenes, some of which have never been implicated in human AD. Over 25 years later, many mouse models have been given an AD-like disease and then ‘cured’ in the lab, only for the treatments to fail in clinical trials. This review argues that small animal models are insufficient for modelling complex disorders such as AD. In order to find effective treatments for AD, we need to create large animal models with brains and lifespan that are closer to humans, and underlying genetics that already predispose them to AD-like phenotypes.

Mitochondrial DNA sequence is frequently used to infer species' boundaries, as divergence is relatively rapid when populations are reproductively isolated. However, the shared history of a non-recombining gene naturally leads to correlation of pairwise differences, resulting in mtDNA clusters that might be mistaken for evidence of multiple species. There are four distinct processes that can explain high levels of mtDNA sequence difference within a single sample. Here, we examine one case in detail as an exemplar to distinguish among competing hypotheses. Within our sample of tree wētā (Hemideina crassidens; Orthoptera), we found multiple mtDNA haplotypes for a protein-coding region (cytb/ND1) that differed by a maximum of 7.9%. From sequencing the whole mitochondrial genome of two representative individuals, we found evidence of constraining selection. Heterozygotes were as common as expected under random mating at five nuclear loci. Morphological traits and nuclear markers did not resolve the mtDNA groupings of individuals. We concluded that the large differences found among our sample of mtDNA sequences were simply owing to a large population size over an extended period of time allowing an equilibrium between mutation and drift to retain a great deal of genetic diversity within a single species.

Hybridization can create the selective force that promotes assortative mating but hybridization can also select for increased hybrid fitness. Gene flow resulting from hybridization can increase genetic diversity but also reduce distinctiveness. Thus the formation of hybrids has important implications for long‐term species coexistence. This study compares the interaction between the tree wētā Hemideina thoracica and its two neighboring species; H. crassidens and H. trewicki. We examined the ratio of parent and hybrid forms in natural areas of sympatry. Individuals with intermediate phenotype were confirmed as first generation hybrids using nine independent genetic markers. Evidence of gene flow from successful hybridization was sought from the distribution of morphological and genetic characters. Both species pairs appear to be largely retaining their own identity where they live in sympatry, each with a distinct karyotype. Hemideina thoracica and H. trewicki are probably reproductively isolated, with sterile F1 hybrids. This species pair shows evidence of niche differences with adult size and timing of maturity differing where Hemideina thoracica is sympatric with H. trewicki. In contrast, evidence of a low level of introgression was detected in phenotypes and genotypes where H. thoracica and H. crassidens are sympatric. We found no evidence of size divergence although color traits in combination with hind tibia spines reliably distinguish the two species. This species pair show a bimodal hybrid zone in the absence of assortative mating and possible sexual exclusion by H. thoracica males in the formation of F1 hybrids.

Natural hybridization between species provides an opportunity to study the mechanisms that maintain independent lineages and may help us understand the process of speciation. The New Zealand tree wētā species Hemideina thoracica produces F 1 hybrids where it lives in sympatry with two closely related species: Hemideina crassidens and Hemideina trewicki. This study looked at the viability and fertility of F 1 hybrid wētā between H. thoracica and H. crassidens that were collected from the wild and kept in captivity. The hybrids appeared to have normal viability from the late juvenile stage, with all male wētā maturing at a late instar. Male F 1 hybrids displayed normal mating behavior and one male produced offspring in captivity. In contrast to Haldane's rule, female F 1 hybrids appeared to be infertile; they refused to mate and did not produce eggs. No evidence of Wolbachia infection was identified in any of the three North Island Hemideina species.