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1. Maternal epigenetic clocks measured during pregnancy do not predict gestational age at delivery or offspring birth outcomes: a replication study in metropolitan Cebu, Philippines

   https://doi.org/10.1186/s13148-022-01296-6  

   Ryan, Calen P. ; Rege, Raviraj J. ; Lee, Nanette R. ; Carba, Delia B. ; Kobor, Michael S. ; MacIsaac, Julie L. ; Lin, David S. ; Atashzay, Parmida ; Kuzawa, Christopher W. ( June 2022 , Clinical Epigenetics)

   Adverse birth outcomes, such as early gestational age and low birth weight, can have lasting effects on morbidity and mortality, with impacts that persist into adulthood. Identifying the maternal factors that contribute to adverse birth outcomes in the next generation is thus a priority. Epigenetic clocks, which have emerged as powerful tools for quantifying biological aging and various dimensions of physiological dysregulation, hold promise for clarifying relationships between maternal biology and infant health, including the maternal factors or states that predict birth outcomes. Nevertheless, studies exploring the relationship between maternal epigenetic age and birth outcomes remain few. Here, we attempt to replicate a series of analyses previously reported in a US-based sample, using a larger similarly aged sample (n = 296) of participants of a long-running study in the Philippines. New pregnancies were identified prospectively, dried blood spot samples were collected during the third trimester, and information was obtained on gestational age at delivery and offspring weight after birth. Genome-wide DNA methylation was assessed with the Infinium EPIC array. Using a suite of 15 epigenetic clocks, we only found one significant relationship: advanced age on the epigenetic clock trained on leptin predicted a significantly earlier gestational age at delivery (β = − 0.15,p = 0.009). Ofmore »the other 29 relationships tested predicting gestational age and offspring birth weight, none were statistically significant. In this sample of Filipino women, epigenetic clocks capturing multiple dimensions of biology and health do not predict birth outcomes in offspring.

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2. The adaptive benefit of evolved increases in hemoglobin-O2 affinity is contingent on tissue O2 diffusing capacity in high-altitude deer mice

   https://doi.org/10.1186/s12915-021-01059-4  

   Wearing, Oliver H. ; Ivy, Catherine M. ; Gutiérrez-Pinto, Natalia ; Velotta, Jonathan P. ; Campbell-Staton, Shane C. ; Natarajan, Chandrasekhar ; Cheviron, Zachary A. ; Storz, Jay F. ; Scott, Graham R. ( June 2021 , BMC Biology)

   Complex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O₂consumption,V̇O₂max, during acute cold exposure) in high-altitude deer mice (Peromyscus maniculatus). We crossed highland and lowland deer mice to produce F₂inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O₂affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O₂transport pathway to examine the links between cardiorespiratory traits andV̇O₂max.

   Physiological experiments revealed that increases in Hb-O₂affinity of red blood cells improved blood oxygenation in hypoxia but were not associated with an enhancement inV̇O₂max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O₂affinity onV̇O₂max in hypoxia was contingent on the capacity for O₂diffusion in active tissues.

   These results suggest that increases in Hb-O₂affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O₂diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O₂affinity is contingent on the capacity to extract O₂from the blood, whichmore »helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.

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3. Identifying Methylation Patterns in Dental Pulp Aging: Application to Age-at-Death Estimation in Forensic Anthropology

   https://doi.org/10.3390/ijms22073717  

   C. Zapico, Sara ; Gauthier, Quentin ; Antevska, Aleksandra ; McCord, Bruce R. ( April 2021 , International Journal of Molecular Sciences)

   Age-at-death estimation constitutes one of the key parameters for identification of human remains in forensic investigations. However, for applications in forensic anthropology, many current methods are not sufficiently accurate for adult individuals, leading to chronological age estimates erring by ±10 years. Based on recent trends in aging studies, DNA methylation has great potential as a solution to this problem. However, there are only a few studies that have been published utilizing DNA methylation to determine age from human remains. The aim of the present study was to expand the range of this work by analyzing DNA methylation in dental pulp from adult individuals. Healthy erupted third molars were extracted from individuals aged 22–70. DNA from pulp was isolated and bisulfite converted. Pyrosequencing was the chosen technique to assess DNA methylation. As noted in previous studies, we found that ELOVL2 and FHL2 CpGs played a role in age estimation. In addition, three new markers were evaluated—NPTX2, KLF14, and SCGN. A set of CpGs from these five loci was used in four different multivariate regression models, providing a Mean Absolute Error (MAE) between predicted and chronological age of 1.5–2.13 years. The findings from this research can improve age estimation, increasing the accuracymore »of identification in forensic anthropology.« less
4. High-altitude rodents have abundant collaterals that protect against tissue injury after cerebral, coronary and peripheral artery occlusion

   https://doi.org/10.1177/0271678X20942609  

   Faber, James E ; Storz, Jay F ; Cheviron, Zachary A ; Zhang, Hua ( April 2021 , Journal of Cerebral Blood Flow & Metabolism)

   Collateral number/density varies widely in brain and other tissues among strains of Mus musculus mice due to differences in genetic background. Recent studies have shown that prolonged exposure to reduced atmospheric oxygen induces additional collaterals to form, suggesting that natural selection may favor increased collaterals in populations native to high-altitude. High-altitude guinea pigs ( Cavia) and deer mice ( Peromyscus) were compared with lowland species of Peromyscus, Mus and Rattus (9 species/strains examined). Collateral density, diameter and other morphometrics were measured in brain where, importantly, collateral abundance reflects that in other tissues of the same individual. Guinea pigs and high-altitude deer mice had a greater density of pial collaterals than lowlanders. Consistent with this, guinea pigs and highlander mice evidenced complete and 80% protection against stroke, respectively. They also sustained significantly less ischemia in heart and lower extremities after arterial occlusion. Vessels of the circle of Willis, including the communicating collateral arteries, also exhibited unique features in the highland species. Our findings support the hypothesis that species native to high-altitude have undergone genetic selection for abundant collaterals, suggesting that besides providing protection in obstructive disease, collaterals serve a physiological function to optimize oxygen delivery to meet oxygen demand when oxygenmore »is limiting.« less
5. A mammalian methylation array for profiling methylation levels at conserved sequences

   https://doi.org/10.1038/s41467-022-28355-z  

   Arneson, Adriana ; Haghani, Amin ; Thompson, Michael J. ; Pellegrini, Matteo ; Kwon, Soo Bin ; Vu, Ha ; Maciejewski, Emily ; Yao, Mingjia ; Li, Caesar Z. ; Lu, Ake T. ; et al ( February 2022 , Nature Communications)

   Infinium methylation arrays are not available for the vast majority of non-human mammals. Moreover, even if species-specific arrays were available, probe differences between them would confound cross-species comparisons. To address these challenges, we developed the mammalian methylation array, a single custom array that measures up to 36k CpGs per species that are well conserved across many mammalian species. We designed a set of probes that can tolerate specific cross-species mutations. We annotate the array in over 200 species and report CpG island status and chromatin states in select species. Calibration experiments demonstrate the high fidelity in humans, rats, and mice. The mammalian methylation array has several strengths: it applies to all mammalian species even those that have not yet been sequenced, it provides deep coverage of conserved cytosines facilitating the development of epigenetic biomarkers, and it increases the probability that biological insights gained in one species will translate to others.