Evolutionary constraint and innovation across hundreds of placental mammals

Abstract

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth’s vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.

Single-fly assemblies fill major phylogenomic gaps across the Drosophilidae Tree of Life

“…The inferred ancestral drosophilid genome is 33.5 Mbp in size, about 10 Mbp larger than the sum of D. melanogaster coding sequences, and contains 97.3% complete BUSCO genes. Moreover, the estimated average substitution rate at 4-fold degenerate sites is 44.8 substitutions/site ( Figure S1 ), suggesting a complete saturation of substitutions at every neutrally evolving site in the alignable genome and base-level resolution of comparative genomics approaches for evolutionary rate estimation (e.g., Christmas et al, 2023). Together, these results demonstrate the immense potential for comparative genomics provided by this dataset even across deep evolutionary timescales.…”

Rapid Adaptation of Cellular Metabolic Rate to the MicroRNA Complements of Mammals and its Relevance to the Evolution of Endothermy

“…Moreover, for three of these 19 microRNAs there were no conserved target sites: miR-105, miR-370 and miR-6715 (Supplementary Table S7). It cannot be excluded that the difference in energy regimes between early- and late-branching placental orders is related to the activities of some combination of the remaining 16 microRNAs, affecting targets unique to, or differentially expressed in later-branching placental mammals (Christmas et al, 2023). However, any such discovery would not shed light on the central question of this study, the nature of the broad correlations across mammals between cellular metabolic rate, the size of the microRNA repertoire, and the predicted number of microRNA-target interactions.…”

“…Our model predicts that compensatory noise suppression by microRNAs should be proportional to body temperature, since temperature is the primary determinant of the rate of protein synthesis, and therefore of intrinsic stochastic translation noise (Thattai and van Oudenaarden, 2001; Ozbudak et al, 2002). Post-transcriptional regulation of gene expression (“mRNA processing”) is the most constrained gene category in the evolutionary history of placental mammals (Christmas et al, 2023), which suggests a significant fitness cost for any loss in the efficiency of the processing of transcripts as mammals evolved faster and more complex regulatory networks.…”

Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution

“…However, fetal microglia GREs were also divergent in human-ancestral lineages. Recent studies on sequence divergence across numerous mammalian species also identified accelerated evolution in environmental response genes, especially immune responses 50,51 . Since microglial identity is driven by environmental stimuli 49 , fetal microglial may have particularly undergone accelerated evolution in humans and their ancestors.…”