The regulation of mitochondrial DNA copy number in glioblastoma cells

As stem cells undergo differentiation, mitochondrial DNA (mtDNA) copy number is strictly regulated in order that specialized cells can generate appropriate levels of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) to undertake their specific functions. It is not understood whether tumor-initiating cells regulate their mtDNA in a similar manner or whether mtDNA is essential for tumorigenesis. We show that human neural stem cells (hNSCs) increased their mtDNA content during differentiation in a process that was mediated by a synergistic relationship between the nuclear and mitochondrial genomes and results in increased respiratory capacity. Differentiating multipotent glioblastoma cells failed to match the expansion in mtDNA copy number, patterns of gene expression and increased respiratory capacity observed in hNSCs. Partial depletion of glioblastoma cell mtDNA rescued mtDNA replication events and enhanced cell differentiation. However, prolonged depletion resulted in impaired mtDNA replication, reduced proliferation and induced the expression of early developmental and pro-survival markers including POU class 5 homeobox 1 (OCT4) and sonic hedgehog (SHH). The transfer of glioblastoma cells depleted to varying degrees of their mtDNA content into immunocompromised mice resulted in tumors requiring significantly longer to form compared with non-depleted cells. The number of tumors formed and the time to tumor formation was relative to the degree of mtDNA depletion. The tumors derived from mtDNA depleted glioblastoma cells recovered their mtDNA copy number as part of the tumor formation process. These outcomes demonstrate the importance of mtDNA to the initiation and maintenance of tumorigenesis in glioblastoma multiforme.     

A quantitative genetic analysis of hibernation emergence date in a wild population of Columbian ground squirrels

The life history schedules of wild organisms have long attracted scientific interest, and, in light of ongoing climate change, an understanding of their genetic and environmental underpinnings is increasingly becoming of applied concern. We used a multi-generation pedigree and detailed phenotypic records, spanning 18 years, to estimate the quantitative genetic influences on the timing of hibernation emergence in a wild population of Columbian ground squirrels (Urocitellus columbianus). Emergence date was significantly heritable [h(2) = 0.22 ± 0.05 (in females) and 0.34 ± 0.14 (in males)], and there was a positive genetic correlation (r(G) = 0.76 ± 0.22) between male and female emergence dates. In adult females, the heritabilities of body mass at emergence and oestrous date were h(2) = 0.23 ± 0.09 and h(2) = 0.18 ± 0.12, respectively. The date of hibernation emergence has been hypothesized to have evolved so as to synchronize subsequent reproduction with upcoming peaks in vegetation abundance. In support of this hypothesis, although levels of phenotypic variance in emergence date were higher than oestrous date, there was a highly significant genetic correlation between the two (r(G) = 0.98 ± 0.01). Hibernation is a prominent feature in the annual cycle of many small mammals, but our understanding of its influences lags behind that for phenological traits in many other taxa. Our results provide the first insight into its quantitative genetic influences and thus help contribute to a more general understanding of its evolutionary significance.     

Polygamy and an absence of fine-scale structure in Dendroctonus ponderosae (Hopk.) (Coleoptera: Curcilionidae) confirmed using molecular markers

An understanding of mating systems and fine-scale spatial genetic structure is required to effectively manage forest pest species such as Dendroctonus ponderosae (mountain pine beetle). Here we used genome-wide single-nucleotide polymorphisms to assess the fine-scale genetic structure and mating system of D. ponderosae collected from a single stand in Alberta, Canada. Fine-scale spatial genetic structure was absent within the stand and the majority of genetic variation was best explained at the individual level. Relatedness estimates support previous reports of pre-emergence mating. Parentage assignment tests indicate that a polygamous mating system better explains the relationships among individuals within a gallery than the previously reported female monogamous/male polygynous system. Furthermore, there is some evidence to suggest that females may exploit the galleries of other females, at least under epidemic conditions. Our results suggest that current management models are likely to be effective across large geographic areas based on the absence of fine-scale genetic structure.     

Genome‐wide set of SNPs reveals evidence for two glacial refugia and admixture from postglacial recolonization in an alpine ungulate

Past glaciation events have played a major role in shaping the genetic diversity and distribution of wild sheep in North America. The advancement of glaciers can isolate populations in ice‐free refugia, where they can survive until the recession of ice sheets. The major Beringian refugium is thought to have held thinhorn sheep (Ovis dalli) populations during times of glacial advance. While isolation in the major refugium can account for much of the genetic and morphological diversity seen in extant thinhorn sheep populations, mounting evidence suggests the persistence of populations in smaller minor refugia. We investigated the refugial origins of thinhorn sheep using ~10 000 SNPs obtained via a cross‐species application of the domestic sheep ovine HD BeadChip to genotype 52 thinhorn sheep and five bighorn sheep (O. canadensis) samples. Phylogenetic inference revealed a distinct lineage of thinhorn sheep inhabiting British Columbia, which is consistent with the survival of a group of thinhorn sheep in a minor refugium separate from the Beringian refugium. Isolation in separate glacial refugia probably mediated the evolution of the two thinhorn sheep subspecies, the white Dall's sheep (O. d. dalli), which persisted in Beringia, and the dark Stone's sheep (O. d. stonei), which utilized the minor refugium. We also found the first genetic evidence for admixture between sheep from different glacial refugia in south‐central Yukon as a consequence of post glacial expansion and recolonization. These results show that glaciation events can have a major role in the evolution of species inhabiting previously glaciated habitats and the need to look beyond established refugia when examining the evolutionary history of such species.     

Post‐weaning parental care increases fitness but is not heritable in North American red squirrels

Most empirical attempts to explain the evolution of parental care have focused on its costs and benefits (i.e. fitness consequences). In contrast, few investigations have been made of the other necessary prerequisite for evolutionary change, inheritance. Here, we examine the fitness consequences and heritability (h²) of a post‐weaning parental care behaviour (territory bequeathal) in a wild population of North American red squirrels. Each year, a subset (average across all years = 19%) of reproductive females bequeathed their territory to a dependent offspring. Bequeathing females experienced higher annual reproductive success and did not suffer a survival cost to themselves relative to those females retaining their territory. Bequeathing females thus realized higher relative annual fitness [ω = 1.18 ± 0.03 (SE)] than nonbequeathing females [ω = 0.96 ± 0.02 (SE)]. Additive genetic influences on bequeathal behaviour, however, were not significantly different from 0 (h² = 1.9 × 10^?3; 95% highest posterior density interval = 3.04 × 10^?8 to 0.37) and, in fact, bequeathal behaviour was not significantly repeatable (R = 2.0 × 10^?3; 95% HPD interval =0–0.27). In contrast, directional environmental influences were apparent. Females were more likely to bequeath in years following low food abundance and when food availability in the upcoming autumn was high. Despite an evident fitness benefit, a lack of heritable genetic variance will constrain evolution of this trait.     

Genetic constraints and sexual dimorphism in immune defense

The absence of continued evolutionary change despite the presence of genetic variation and directional selection is very common. Genetic correlations between traits can reduce the evolvability of traits. One intriguing example might be found in a sexual conflict over sexually dimorphic traits: a common genetic architecture constrains the response to selection on a trait subjected to sexually asymmetric selection pressures. Here we show that males and females of the mealworm beetle Tenebrio molitor differ in the quantitative genetic architecture of four traits related to immune defense and condition. Moreover, high genetic correlations between the sexes constitute a genetic constraint to the evolution of sexual dimorphism in immune defense. Our results suggest a general mechanism by which sexual conflict can promote evolutionary stasis. We furthermore show negative genetic correlations, strong indications of trade-offs, between immune traits for two pairs of traits in females.     

Age-dependent sexual selection in bighorn rams.

Although mating systems and sexual selection have been intensively studied in ungulate model systems, very few studies have combined genetic paternity analysis with individual phenotypic data over several breeding seasons. We used microsatellite paternity analysis to determine the parentage of 83 bighorn sheep (Ovis canadensis) born between 1995 and 2000 at Ram Mountain, Alberta, Canada. We could assign the paternity of 64 lambs at a high level of statistical confidence (95%). Within each season, the most successful ram sired an average of 35.5% of the lambs with assigned paternity, and a single ram sired 26.1% of all lambs over the six mating seasons. Although a few large-horned, mature (age 8+ years) rams had very high reproductive success, younger rams sired ca. 50% of the lambs. Mixed-effects models indicated that mating success increases as a nonlinear function of age, with horn length increasingly positive in correlation with mating success in older rams. These results indicate that young or small rams possibly achieve mating success through alternative mating tactics that are less dependent on body and weapon size, such as coursing and blocking. Sexual selection is therefore likely to have age-dependent effects on traits such as agility, body and horn size.     

Age-dependent genetic effects on a secondary sexual trait in male Alpine ibex, Capra ibex

Secondary sexual traits, such as horns in ungulates, may be good indicators of genetic quality because they are costly to develop. Genetic effects on such traits may be revealed by examining correlations between multilocus heterozygosity (MLH) and trait value. Correlations between MLH and fitness traits, termed heterozygosity-fitness correlations (HFC), may reflect inbreeding depression or associative overdominance of neutral microsatellite loci with loci directly affecting fitness traits. We investigated HFCs for horn growth, body mass and faecal counts of nematode eggs in wild Alpine ibex (Capra ibex). We also tested if individual inbreeding coefficients (f') estimated from microsatellite data were more strongly correlated with fitness traits than MLH. MLH was more strongly associated with trait variation than f'. We found HFC for horn growth but not for body mass or faecal counts of nematode eggs. The effect of MLH on horn growth was age-specific. The slope of the correlation between MLH and yearly horn growth changed from negative to positive as males aged, in accordance with the mutation accumulation theory of the evolution of senescence. Our results suggest that the horns of ibex males are an honest signal of genetic quality.     

Pulmonary aspiration in preschool children with cystic fibrosis

Pulmonary aspiration of gastric refluxate (PAGR) has been demonstrated in association with pulmonary inflammation in school aged children with Cystic Fibrosis (CF). We sought to determine if similar findings were present in preschool children. Pepsin was measured in Broncho-alveolar lavage (BAL) fluid collected from clinically stable preschool children with CF and controls. Elevated pepsin levels were found in a subgroup of children with CF, but this was not found to be associated with pulmonary infection, pulmonary inflammation or respiratory or gastrointestinal symptoms.