Seasonality and Sex-Biased Fluctuation of Birth Weight in Tibetan Populations

Abstract

Birth weight (BW) is a key determinant of infant mortality. Previous studies have reported seasonal fluctuation of BW. However, the responsible environmental factors remain disputable. High-altitude environment provides a great opportunity to test the current hypotheses due to its distinctive climate conditions. We collected BW data of ~ 9000 Tibetan singletons born at Lhasa (elevation: 3660 m) from 2014 to 2018. Using regression models, we analyzed BW seasonality of highland Tibetans. Multivariate models with meteorological factors as independent variables were employed to examine responsible environmental factors accounting for seasonal variation. We compared BW, low-BW prevalence and sex ratio between highland and lowland populations, and we observed a significant seasonal pattern of BW in Tibetans, with a peak in winter and a trough in summer. Notably, there is a marked sex-biased pattern of BW seasonality (more striking in males than in females). Sunlight exposure in the 3rd trimester and barometric pressure exposure in the 2nd trimester are significantly correlated with BW, and the latter can be explained by seasonal change of oxygen partial pressure. In particular, due to the male-biased BW seasonality, we found a more serious BW reduction and higher prevalence of low-BW in males, and a skewed sex ratio in highlanders. The infant BW of highland Tibetans has a clear pattern of seasonality. The winter BW is larger than the summer BW, due to the longer sunlight exposure during the late-trimester. Male infants are more sensitive to hypoxia than female infants during the 2nd trimester, leading to more BW reduction and higher mortality.

Sex-biased regulatory changes in the placenta of native highlanders contribute to adaptive fetal development

“…Therefore, we speculate that the selective pressure on EPAS1 is likely through its effect on hemoglobin, rather than directly on the reproductive traits. The down-regulation of EPAS1 in placenta likely reflects a blunted hypoxic response that may improve vasodilation of UC for better blood flow, and eventually leading to the higher BW in Tibetans (He et al, 2023 ). For EGLN1, another well-known gene in Tibetans, we detected between-population expression difference in the male UC layer, but not in other placental layers.…”

“…Han Chinese moving to high altitude), reflected by the higher newborn BW and the lower prenatal and postnatal mortality (Beall et al, 2004 ;Moore et al, 2011 ). As expected, Tibetans performed better than Han migrants during fetal development (He et al, 2023 ;Julian et al, 2009 ;Moore et al, 2011 ;Moore et al, 2001a ). Previous genomic studies have identified a group of genes potentially contributing to the genetic adaptation of Tibetans to high-altitude environments, and these studies were mostly focused on the blood and cardiopulmonary systems of adult Tibetans (Beall et al, 2010a ;Bigham et al, 2010 ;Deng et al, 2019 ;Peng et al, 2011 ;Simonson et al, 2010 ;Song et al, 2020 ;Xiang et al, 2013 ;Xu et al, 2011 ;Yang et al, 2017 ;Yi et al, 2010 ).…”

“…The gene expression level of GHR in the VF layer is positively correlated with FUH (R = 0.44, p = 0.017) of the female newborns, an indicator of fetal growth (Morse et al, 2009 ), but not the male newborns (Figure S7). Consistently, it is up-regulated in Tibetans, corresponding to the higher FUH in Tibetans (He et al, 2023 ). Interestingly, the expression pattern of GHR mirrors GH (growth hormone) in placenta early development and embryonic growth (Harvey and Baudet, 2014 ).…”

“…After applying a stringent quality control (Methods), we kept 448 placental transcriptome data, and each sample contains ∼27 million reads on average (sample details in Table S1). In addition, we obtained the genome-wide variants of these mothers and their newborns from our previous studies (He et al, 2023 ;Zheng et al, 2023 ).…”

“…For phenotypic data, we made a systematical comparison of reproductive outcomes in our previous studies (He et al, 2023;He et al, 2022). We proved that polygenic adaptation of reproduction in Tibetans tends to reduce the chance of preterm birth and eliminate the restriction on fetal development at high altitude.…”