Biological stability of DNA methylation measurements over varying intervals of time and in the presence of acute stress.

Identifying factors that influence the stability of DNA methylation measurements across biological replicates is of critical importance in basic and clinical research. Using a within-person between-group experimental design (n = 31, number of observations = 192), we report the stability of biological replicates over a variety of unique temporal scenarios, both in the absence and presence of acute psychosocial stress, and between individuals who have experienced early life adversity (ELA) and non-exposed individuals. We found that varying time intervals, acute stress, and ELA exposure influenced the stability of repeated DNA methylation measurements. In the absence of acute stress, probes were less stable as time passed; however, stress exerted a stabilizing influence on probes over longer time intervals. Compared to non-exposed individuals, ELA-exposed individuals had significantly lower probe stability immediately following acute stress. Additionally, we found that across all scenarios, probes used in most epigenetic-based algorithms for estimating epigenetic age or immune cell proportions had average or below-average stability, except for the Principal Component and DunedinPACE epigenetic ageing clocks, which were enriched for more stable probes. Finally, using highly stable probes in the absence of stress, we identified multiple probes that were hypomethylated in the presence of acute stress, regardless of ELA status. Two hypomethylated probes are located near the transcription start site of the glutathione-disulfide reductase gene (GSR), which has previously been shown to be an integral part of the stress response to environmental toxins. We discuss implications for future studies concerning the reliability and reproducibility of DNA methylation measurements.Abbreviations: DNAm - DNA methylation, CpG - 5'-cytosine-phosphate-guanine-3,' ICC - Interclass correlation coefficient, ELA - Early-life adversity, PBMCs - Peripheral blood mononuclear cells, mQTL - Methylation quantitative trait loci, TSS - Transcription start site, GSR - Glutathione-disulfide reductase gene, TSST - Trier social stress test, PC - Principal component.

Immune cell dynamics in response to an acute laboratory stressor: a within-person between-group analysis of the biological impact of early life adversity.

Early life adversity (ELA) is a risk factor for early onset morbidities and mortality, a relationship that may be driven in part by immune system dysregulation. One mechanism of dysregulation that has yet to be fully examined in the context of ELA is alterations to immune cell dynamics in response to acute stress. Using a within-person between-group experimental design, we investigated stress-induced changes in immune cell populations, and how these changes may be altered in individuals with a history of ELA. Participants were young adults (N = 34, aged 18-25 years, 53% female, 47% with a history of ELA). Complete immune cell counts were measured at four time-points over a 5-hour window across two sessions (Trier Social Stress Test [TSST] vs. no-stress) separated by a week. Across all participants, total white blood cells increased over time (F(3,84)=38.97, p < .001) with a greater increase in response to the TSST compared to the no-stress condition at 240 minutes post-test (b = 0.43±.19; t(179)=2.22, p = .027). This pattern was mirrored by neutrophil counts. Lymphocyte counts were initially depressed by TSST exposure (b =-205±.67; t(184)=-3.07, p = .002) but recovered above baseline. ELA status was associated with higher stress-induced immune cell counts, a difference likely driven by increases in neutrophils (F(1,22)=4.45, p = .046). Overall, these results indicate differential immune cell dynamics in response to acute stress in individuals with a history of ELA. This points to altered immune system functioning in the context of stress, a finding that may be driving increased morbidity and mortality risk for ELA-exposed individuals.

Intergenerational transmission of childhood trauma? Testing cellular aging in mothers exposed to sexual abuse and their children.

BACKGROUND: Exposure to maltreatment in childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) was associated with telomere length (TL) in adult females. We further tested the hypothesis of intergenerational transmission of CSA-related effects by measuring TL in both CSA-exposed and non-exposed mothers and their children. METHODS: Participants were a subset of females and their children in a prospective-longitudinal cohort study of sexually abused females and a demographically comparable control group from the same Washington, D.C. area. TL was measured using qPCR in both leukocyte and buccal samples from females (N = 108, mean age 36.3 years) and buccal samples from their children (N = 124, mean age 10.5 years). Multilevel models were used to test associations between CSA-exposure and TL measured in leukocytes and buccal tissue in females and to test the intergenerational effect of maternal-CSA exposure on age-adjusted TL in their children. RESULTS: CSA-exposure was not associated with TL in adult females. Maternal TL and biological sex were significant predictors of child TL such that longer maternal TL predicted longer TL in children, and female children had longer TL than male children. However, maternal-CSA exposure did not predict TL in children. DISCUSSION: CSA-exposure was not associated with TL in this cohort of middle-aged females, nor was there evidence for an intergenerational effect of maternal-CSA exposure on child TL. This finding is in line with some previous results on CSA and adult TL. Previous significant results associating child maltreatment with shorter TL may be capturing a population of individuals exposed to either multiple types of maltreatment compared to controls with no childhood adversity, or maltreatment in childhood with concurrent TL measurements.

Testing three hypotheses about effects of sensitive-insensitive parenting on telomeres.

Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter case, most work has relied on retrospective measures of early life stressors. The Dutch research (n = 193) presented herein tested 3 hypotheses prospectively regarding effects of sensitive-insensitive parenting during the first 2.5 years on telomere length at age 6, when first measured, and change over the following 4 years. It was predicted that (1) less sensitive parenting would predict shorter telomeres and greater erosion and that such effects would be most pronounced in children (2) exposed to prenatal stress and/or (3) who were highly negatively emotional as infants. Results revealed, only, that prenatal stress amplified parenting effects on telomere change-in a differential-susceptibility-related manner: Prenatally stressed children displayed more erosion when they experienced insensitive parenting and less erosion when they experienced sensitive parenting. Mechanisms that might initiate greater postnatal plasticity as a result of prenatal stress are highlighted and future work outlined. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Facial masculinity does not appear to be a condition-dependent male ornament and does not reflect MHC heterozygosity in humans.

Recent studies have called into question the idea that facial masculinity is a condition-dependent male ornament that indicates immunocompetence in humans. We add to this growing body of research by calculating an objective measure of facial masculinity/femininity using 3D images in a large sample (n = 1,233) of people of European ancestry. We show that facial masculinity is positively correlated with adult height in both males and females. However, facial masculinity scales with growth similarly in males and females, suggesting that facial masculinity is not exclusively a male ornament, as male ornaments are typically more sensitive to growth in males compared with females. Additionally, we measured immunocompetence via heterozygosity at the major histocompatibility complex (MHC), a widely-used genetic marker of immunity. We show that, while height is positively correlated with MHC heterozygosity, facial masculinity is not. Thus, facial masculinity does not reflect immunocompetence measured by MHC heterozygosity in humans. Overall, we find no support for the idea that facial masculinity is a condition-dependent male ornament that has evolved to indicate immunocompetence.

Correction: Investigating the case of human nose shape and climate adaptation.

[This corrects the article DOI: 10.1371/journal.pgen.1006616.].

Genome-wide mapping of global-to-local genetic effects on human facial shape.

Genome-wide association scans of complex multipartite traits like the human face typically use preselected phenotypic measures. Here we report a data-driven approach to phenotyping facial shape at multiple levels of organization, allowing for an open-ended description of facial variation while preserving statistical power. In a sample of 2,329 persons of European ancestry, we identified 38 loci, 15 of which replicated in an independent European sample (n = 1,719). Four loci were completely new. For the others, additional support (n = 9) or pleiotropic effects (n = 2) were found in the literature, but the results reported here were further refined. All 15 replicated loci highlighted distinctive patterns of global-to-local genetic effects on facial shape and showed enrichment for active chromatin elements in human cranial neural crest cells, suggesting an early developmental origin of the facial variation captured. These results have implications for studies of facial genetics and other complex morphological traits.

Investigating the case of human nose shape and climate adaptation.

The evolutionary reasons for variation in nose shape across human populations have been subject to continuing debate. An import function of the nose and nasal cavity is to condition inspired air before it reaches the lower respiratory tract. For this reason, it is thought the observed differences in nose shape among populations are not simply the result of genetic drift, but may be adaptations to climate. To address the question of whether local adaptation to climate is responsible for nose shape divergence across populations, we use Qst-Fst comparisons to show that nares width and alar base width are more differentiated across populations than expected under genetic drift alone. To test whether this differentiation is due to climate adaptation, we compared the spatial distribution of these variables with the global distribution of temperature, absolute humidity, and relative humidity. We find that width of the nares is correlated with temperature and absolute humidity, but not with relative humidity. We conclude that some aspects of nose shape may indeed have been driven by local adaptation to climate. However, we think that this is a simplified explanation of a very complex evolutionary history, which possibly also involved other non-neutral forces such as sexual selection.

Exploring the Underlying Genetics of Craniofacial Morphology through Various Sources of Knowledge.

The craniofacial complex is the billboard of sorts containing information about sex, health, ancestry, kinship, genes, and environment. A thorough knowledge of the genes underlying craniofacial morphology is fundamental to understanding craniofacial biology and evolution. These genes can also provide an important foundation for practical efforts like predicting faces from DNA and phenotype-based facial diagnostics. In this work, we focus on the various sources of knowledge regarding the genes that affect patterns of craniofacial development. Although tremendous successes recently have been made using these sources in both methodology and biology, many challenges remain. Primary among these are precise phenotyping techniques and efficient modeling methods.