Harvey, L. M. R. | bioRxiv Science

bioRxiv2022

The human placenta exhibits a unique transcriptomic void

We have recently demonstrated that the human placenta exhibits a unique genomic architecture with an unexpectedly high mutation burden(Coorens et al. 2021) and it is also well recognized that the placenta uniquely expresses many genes(Gong et al. 2021). However, the placenta is relatively understudied in systematic comparisons of gene expression in different organs. The aim of the present study was to identify transcripts which were uniquely absent or depleted, comparing the placenta with 46 other human organs. Here we show that 40/46 of the other organs had no transcripts which were selectively depleted and that of the remaining six, the liver had the largest number with 26. In contrast, the term placenta had 762 depleted transcripts. Gene Ontology analysis of this depleted set highlighted multiple pathways reflecting known unique elements of placental physiology. However, analysis of term samples demonstrated massive over representation of genes involved in mitochondrial function (P=5.8x10-10), including PGC-1 - the master regulator of mitochondrial biogenesis, and genes involved in polyamine metabolism (P=2.1x10-4). We conclude that the term placenta exhibits a unique metabolic environment.

genomics↗

bioRxiv2021

Somatic mutation rates scale with lifespan across mammals

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species and on long-standing hypotheses regarding the evolution of somatic mutation rates and their role in cancer and ageing. Here, we used whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found somatic mutagenesis to be dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species. Remarkably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied displaying a comparable association. Despite widely different life histories among the species surveyed, including [~]30-fold variation in lifespan and [~]40,000-fold variation in body mass, the somatic mutation burden at the end of lifespan varied only by a factor of [~]3. These data unveil common mutational processes across mammals and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.

genomics↗