1. Monitoring the response of wild mammal populations to threatening processes is fundamental to effective conservation management. This is especially true for infectious diseases, which may have dynamic and therefore unpredictable interactions with their host. 2. We investigate the long-term impact of a transmissible cancer, devil facial tumour disease (DFTD), on the endemic Tasmanian devil. We analyse trends in devil spot-light counts and density across the area impacted by the disease. We investigate the demographic parameters which might be driving these trends, and use spatial capture-recapture models to examine whether DFTD has affected home range size. 3. We found that devils have declined by an average of 77% in areas affected by DFTD, and that there is a congruent trend of ongoing small decline in spotlight counts and density estimates. Despite this, devils have persisted to date within each of nine monitoring sites. One site is showing as yet unexplained small increases in density 8–10 years after the emergence of DFTD. 4. We also found the prevalence of DFTD has not abated despite large declines in density and that diseased sites continue to be dominated by young devils. The long-term impact of the disease has been partially offset by increased fecundity in the form of precocial breeding in 1-year-old females, and more pouch young per female in diseased sites. The lower densities resulting from DFTD did not affect home range size. 5. Synthesis and applications. Transmission of devil facial tumour disease continues despite large declines in devil density over multiple generations. Plasticity in life history traits has ameliorated the impact of devil facial tumour disease, however broad-scale trends in density show ongoing decline. In light of this, devil facial tumour disease and the impact of stochastic events on the reduced densities wrought by the disease, continue to threaten devils. In the absence of methods to manage disease in wild populations, we advocate managing the low population densities resulting from disease rather than disease per se.

Identifying the genetic architecture of complex phenotypes is a central goal of modern biology, particularly for disease-related traits. Genome-wide association methods are a classical approach for identifying the genomic basis of variation in disease phenotypes, but such analyses are particularly challenging in natural populations due to sample size difficulties. Extensive mark-recapture data, strong linkage disequilibrium and a lethal transmissible cancer make the Tasmanian devil (Sarcophilus harrisii) an ideal model for such an association study. We used a RAD-capture approach to genotype 624 devils at ~16,000 loci and then used association analyses to assess the heritability of three cancer-related phenotypes: infection case-control (where cases were infected devils and controls were devils that were never infected), age of first infection and survival following infection. The SNP array explained much of the phenotypic variance for female survival (>80%) and female case-control (>61%). We found that a few large-effect SNPs explained much of the variance for female survival (~5 SNPs explained >61% of the total variance), whereas more SNPs (~56) of smaller effect explained less of the variance for female case-control (~23% of the total variance). By contrast, these same SNPs did not account for a significant proportion of phenotypic variance in males, suggesting that the genetic bases of these traits and/or selection differ across sexes. Loci involved with cell adhesion and cell-cycle regulation underlay trait variation, suggesting that the devil immune system is rapidly evolving to recognize and potentially suppress cancer growth through these pathways. Overall, our study provided necessary data for genomics-based conservation and management in Tasmanian devils.

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Size at birth is an important determinant of perinatal survival and has also been associated with the risk for cardiovascular disease and type 2 diabetes in adult life. Common genetic variation that regulates fetal growth could therefore influence perinatal survival and predispose to the development of adult disease. We have tested the insulin gene (INS) variable number of tandem repeats (VNTR) locus, which in Caucasians has two main allele sizes (class I and class III; ref. 3), as a functional candidate polymorphism for association with size at birth, as it has been shown to influence transcription of INS (refs 3-5). In a cohort of 758 term singletons (Avon Longitudinal Study of Pregnancy and Childhood; ALSPAC) followed longitudinally from birth to 2 years, we detected significant genetic associations with size at birth: class III homozygotes had larger mean head circumference (P=0.004) than class I homozygotes. These associations were amplified in babies who did not show postnatal realignment of growth (45%), and were also evident for length (P=0.015) and weight (P=0.009) at birth. The INS VNTR III/II genotype might have bestowed a perinatal survival during human history by conferring larger size at birth. Common genetic variation of this kind may contribute to reported associations between birth size and adult disease.

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.

The rising prevalence of Type II (non-insulin-dependent) diabetes and obesity worldwide poses a serious challenge to human health and incomplete understanding of the aetiological basis of these closely related metabolic conditions is a major impediment to improved management. There is considerable evidence to suggest that primary abnormalities in energy balance contribute to the pathogenesis of diabetes and obesity [1]. Reduced energy expenditure is correlated with subsequent weight gain [2] and normoglycaemic women at increased risk of future diabetes have defective post-prandial thermogenesis [3,4]. Diabetologia (2000) Abstract Aims/hypothesis. Uncoupling proteins are mitochondrial transmembrane carriers implicated in the regulation of energy balance. Dysfunction of UCP3 (the predominant uncoupling protein in skeletal muscle) might therefore be expected to reduce thermogenic capacity, alter energy homeostasis and influence predisposition to obesity and Type II (non-insulin-dependent) diabetes mellitus. A variant in the putative promoter region of UCP3 (±55 c®t) has recently been identified, and an association with obesity reported in French subjects. Our aim was to study the pathophysiological role of this variant in diabetes-related and obesity-related traits using two distinct ethnic populations. Methods. The ±55 c®t variant was genotyped in 85 South Indian and 150 European parent-offspring trios ascertained through Type II diabetic probands and in 455 South Indian subjects initially recruited to an urban survey into the prevalence of diabetes. Results. In South Indian and European parent-offspring trios there was no preferential transmission of either allele at the ±55 c®t polymorphism to diabetic offspring (South Indians, p = 0.60; Europeans, p = 0.15). When family members were analysed for intermediate traits, the t-allele was associated with increased waist-to-hip ratio but only in females (South Indian mothers p = 0.036, daughters p = 0.032: European mothers p = 0.037, daughters p = 0.14). These findings were replicated in South Indian females from the population-based survey (p = 0.039). Conclusion/interpretation. The consistent association between the t-allele at this locus and increased waist-to-hip ratio in women from three separate data sets indicates that variation at this polymorphism (or another locus with which it is in linkage disequilibrium) influences fat distribution but that this effect is restricted to females. [Diabetologia (2000)

Context Conservation management relies on baseline demographic data of natural populations. For Tasmanian devils (Sarcophilus harrisii), threatened in the wild by two fatal and transmissible cancers (devil facial tumour disease DFTD: DFT1 and DFT2), understanding the characteristics of healthy populations is crucial for developing adaptive management strategies to bolster populations in the wild. Aims Our analysis aims to evaluate contemporary reproductive rates for wild, DFTD-free Tasmanian devil populations, and to provide a baseline with which to compare the outcome of current translocation activities. Methods We analysed 8 years of field-trapping data, including demographics and reproductive rates, across 2004–16, from the largest known DFTD-free remnant population at Woolnorth, Tasmania. Key results Surprisingly, we found a dramatic and statistically significant decline in female breeding rate when comparing data collected from 2004–2009 with data from 2014–2016. Unfortunately we do not have any data from the intermediate years. This decline in breeding rate was accompanied by a subtle but statistically significant decline in litter sizes. These changes were not associated with a change in body condition over the same period. Furthermore, we could not attribute the decline in breeding to a change in population size or sex ratio. Preliminary analysis suggested a possible association between annual breeding rate and coarse measures of environmental variation (Southern Oscillation Index), but any mechanistic associations are yet to be determined. Conclusions The decline in breeding rates was unexpected, so further monitoring and investigation into potential environmental and/or biological reasons for the decline in breeding rate are recommended before the arrival of DFTD at Woolnorth. Implications Our results provide valuable data to support the conservation management of Tasmanian devils in their native range. They also highlight the importance of continued monitoring of ‘safe’ populations, in the face of significant threats elsewhere.

OBJECTIVE: To investigate whether genetic variation at the UCP3 locus contributes to human obesity. SUBJECTS: Ninety-one obese children (BMI b 4 standard deviations from age related mean) and 419 Caucasian adults from the Isle of Ely Study. DESIGN: Single strand conformation polymorphism (SSCP) analysis was used to scan the coding region of the UCP3 gene in 91 severely obese children. A common polymorphism identi®ed in this gene (c-55t) has been shown to associate with lower UCP3 mRNA expression. Polymerase chain reaction-based forced restriction digestion was used to detect this allele in Caucasian adults. Multiple regression analysis was used to determine associations between the c-55t genotype and anthropometric, energetic and biochemical indices relevant to obesity. MEASUREMENTS: For the obese children, SSCP analysis and sequencing of variants were carried out. For the Isle of Ely Study, c-55t genotype and anthropometric (body mass index, waist ± hip ratio, percentage body fat), energetic (dietary fat intake, physical activity index, adjusted metabolic rate, maximum oxygen consumption) and biochemical indices (pre-and postglucose challenge plasma triglycerides, non-esteri®ed fatty acids, insulin and glucose) were determined. RESULTS: A previously reported missense mutation (V102I) was detected in a single obese Afro-Carribean child. Twenty-one percent of the genes examined in the Isle of Ely study carried the c-55t promoter variant. Age-adjusted body mass index (BMI) was signi®cantly (P 0.0037) lower in carriers of this variant. CONCLUSION: Mutations in the coding sequence of UCP3 are unlikely to be a common monogenic cause of severe human obesity. In a Caucasian population the UCP3 c-55t polymorphism is negatively associated with BMI.