A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing

Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.

Food Preferences in a Greenlandic Population

Objectives The overall aim was to describe food reward in an Inuit population in Greenland. More specifically, the objective was to first test the differences in food reward for sweet relative to savory food (taste bias) after four weeks on a traditionally Inuit diet (TID) vs a Westernized diet (WD). If no differences in taste bias were found between diet groups, we aimed to describe food reward in a pooled sample (median [IQR]). We hypothesized that participants would have higher preferences for sweet compared to savory foods. Methods After a dietary intervention in Greenland (20% of foods provided), we measured behavioral components of food reward using the Leeds Food Preference Questionnaire. The reward components, explicit liking and implicit wanting, were measured in response to images of Western foods varying in fat content and taste after four weeks on either TID or WD. A positive bias score reflected preference for sweet over savory, and oppositely a negative bias score reflected preference for savory over sweet foods. Results Participant characteristics were similar in the two diet groups (age (mean (SD): TID = 58.1 (11.5) vs. WD = 55.4 (9.5) years); sex: TID = 50% vs. WD = 54% women; body mass index (mean (SD): TID = 26.6 (5.5) vs. WD = 27.9 (4.7) kg/m2). In these preliminary, unadjusted analyses, we found no differences in explicit liking (P = 0.77) or implicit wanting (P = 0.70) bias score for sweet over savory foods after four weeks following either TID (n = 26) or WID (n = 24). Altogether, participants in the two diet groups had a greater explicit liking (−11.5 [−19.9; −2.8]) and implicit wanting (−21.6 [−44.2; −5.2]) for savory compared to sweet foods. Conclusions This is the first study to examine explicit and implicit aspects of food reward in an Inuit population. Contrary to our hypothesis, this population did not prefer sweet over savory Western foods. Funding Sources The study was supported by unrestricted grants from The Novo Nordisk Foundation. Royal Greenland and the supermarket chains Kalaallit Nunaanni Brugseni & Pilersuisoq supported the study with foods and food logistics.

Early-Life Exposure to Environmental Contaminants Perturbs the Sperm Epigenome and Induces Negative Pregnancy Outcomes for Three Generations via the Paternal Lineage

Due to the grasshopper effect, the Arctic food chain in Canada is contaminated with persistent organic pollutants (POPs) of industrial origin, including polychlorinated biphenyls and organochlorine pesticides. Exposure to POPs may be a contributor to the greater incidence of poor fetal growth, placental abnormalities, stillbirths, congenital defects and shortened lifespan in the Inuit population compared to non-Aboriginal Canadians. Although maternal exposure to POPs is well established to harm pregnancy outcomes, paternal transmission of the effects of POPs is a possibility that has not been well investigated. We used a rat model to test the hypothesis that exposure to POPs during gestation and suckling leads to developmental defects that are transmitted to subsequent generations via the male lineage. Indeed, developmental exposure to an environmentally relevant Arctic POPs mixture impaired sperm quality and pregnancy outcomes across two subsequent, unexposed generations and altered sperm DNA methylation, some of which are also observed for two additional generations. Genes corresponding to the altered sperm methylome correspond to health problems encountered in the Inuit population. These findings demonstrate that the paternal methylome is sensitive to the environment and that some perturbations persist for at least two subsequent generations. In conclusion, although many factors influence health, paternal exposure to contaminants plays a heretofore-underappreciated role with sperm DNA methylation contributing to the molecular underpinnings involved.

Analysis of Hepatitis B Virus Genotype D in Greenland Suggests the Presence of a Novel Quasi-Subgenotype

A disproportionate number of Greenland's Inuit population are chronically infected with Hepatitis B virus (HBV; 5–10%). HBV genotypes B and D are most prevalent in the circumpolar Arctic. Here, we report 39 novel HBV/D sequences from individuals residing in southwestern Greenland. We performed phylodynamic analyses with ancient HBV DNA calibrators to investigate the origin and relationship of these taxa to other HBV sequences. We inferred a substitution rate of 1.4 × 10−5 [95% HPD 8.8 × 10−6, 2.0 × 10−5] and a time to the most recent common ancestor of 629 CE [95% HPD 37–1138 CE]. The Greenland taxa form a sister clade to HBV/D2 sequences, specifically New Caledonian and Indigenous Taiwanese sequences. The Greenland sequences share amino acid signatures with subgenotypes D1 and D2 and ~97% sequence identity. Our results suggest the classification of these novel sequences does not fit within the current nomenclature. Thus, we propose these taxa be considered a novel quasi-subgenotype.

Living in the South, Caring in the North: Exploring Inuit Women’s Care Responsibilities

The increased Inuit population in Canadian Metropolitan Areas (CMA) has recently gained attention among the scientific community as well as within Inuit organizations. However, existing literature has overlooked the distinct experience of Inuit women and, more significantly, the importance of care responsibilities in understanding women’s mobility. This study examines the relocation experiences of 46 Inuit women across five CMAs, and the role care sites play in initiating women’s relocation to cities. Results show the key role caregiving responsibilities play in Inuit women’s decisions to move to southern urban areas, as dysfunctional care spaces in the North push them away from their communities, and the potential for safer care sites in the South act as a pulling factor.

Analysis of Hepatitis B virus genotype D in Greenland suggests presence of a novel subgenotype

A disproportionate amount of Greenland’s Inuit population is chronically infected with Hepatitis B virus (HBV; 5-10%). HBV genotypes B and D are most prevalent in the circumpolar Arctic. Here, we report 39 novel HBV/D sequences from individuals residing in southwestern Greenland. We performed phylodynamic analyses with ancient HBV DNA calibrators to investigate the origin and relationship of these taxa to other HBV sequences. We inferred a substitution rate of 1.4×10−5 [95% HPD 8.8×10−6, 2.0×10−5] and a time to the most recent common ancestor of 629 CE [95% HPD 37-1138 CE]. The Greenland taxa form a sister clade to HBV/D2 sequences, specifically New Caledonian and Indigenous Taiwanese samples. The Greenland sequences share amino acid signatures with subgenotypes D1 and D2, and approximately 98% sequence identity. Our results suggest the classification of these novel sequences does not fit within the current nomenclature. Thus, we propose these taxa be a novel subgenotype.