Effect of genomic imprinting in placentas on maternal transmission of growth phenotypes to offspring in a multigenerational human cohort study

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Strassmann, BI PROJECT SUMMARY Non-communicable diseases (NCDs) are the leading causes of ill health on a global scale and are responsible for seven out of ten deaths. Epigenetic mechanisms play a major role in the developmental origins of NCDs and can transfer information about maternal nutrition to offspring. Genomic imprinting is a mechanism of epigenetic regulation that leads to monoallelic expression of genes based on parent of origin, without regard to DNA sequence. Currently, a major obstacle in the genomic imprinting field is the total lack of longitudinal data on human phenotypes. Such data are needed for understanding why there is so much variability in imprinting between individuals and the functional significance of this variability. This study will test the innovative hypothesis that natural variation in imprinting transmits maternal growth and life history phenotypes to offspring. The researchers collected longitudinal phenotypic data on two generations of mothers and offspring in Mali, West Africa (1998 to 2020). The maternal phenotypes of interest are relevant to NCDs and include body mass index, height, stunting, height-for-age z-score (HAZ) trajectories in childhood, age at puberty and menarche, as well as pre-pregnancy BMI and fat stores (buttocks circumference). The offspring phenotypes include birth parameters, growth trajectories for BMI, height, and HAZ to age 5 years, age at weaning, and age at attainment of developmental milestones for locomotion (sitting without support, standing alone, and walking alone). When the offspring were born, the researchers collected 470 placentas, of which 385 passed quality controls. This study has three specific aims. Aim 1: Test the effects of longitudinally measured maternal nutrition, growth, and life history phenotypes on imprinting in 259 genes in placentas delivered at term. This aim will require the generation of a high-resolution dataset on allele specific expression (ASE) in 385 placentas using a high throughput sequencing technique called “targeted RNAseq.” The targeting region includes the exons of all genes that are known to be imprinted in humans or that are closely associated with differentially methylated regions (DMRs). Aim 2: Test the effects of longitudinally measured maternal nutrition, growth, and life history phenotypes on methylation and hydroxymethylation of both ubiquitous and placenta specific DMRs. Using targeted DNA-methyl sequencing, the researchers will determine the variability in methylation on 1,695 DMRs in 385 placentas. Aim 3: Test the effects of epigenetic read-outs (ASE and DNA methylation) on offspring phenotypes. The results of this study will be significant for understanding why there is so much inter- individual variation in imprinting and DNA methylation. This variability, which presently is of unknown significance, has the potential to be at the crux of diseases that are rooted in deficits and surfeits of maternal nutrition. In sum, this study will provide new insight into the developmental origins of health and disease.