Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Single nucleotide polymorphism (SNP) arrays for domestic cattle have catalyzed the identification of genetic markers associated with complex traits for inclusion in modern breeding and selection programs. Using actual and imputed Illumina 778K genotypes for 3887 U.S. beef cattle from 3 populations (Angus, Hereford, SimAngus), we performed genome-wide association analyses for feed efficiency and growth traits including average daily gain (ADG), dry matter intake (DMI), mid-test metabolic weight (MMWT), and residual feed intake (RFI), with marker-based heritability estimates produced for all traits and populations. Moderate and/or large-effect QTL were detected for all traits in all populations, as jointly defined by the estimated proportion of variance explained (PVE) by marker effects (PVE ≥ 1.0%) and a nominal P-value threshold (P ≤ 5e-05). Lead SNPs with PVE ≥ 2.0% were considered putative evidence of large-effect QTL (n = 52), whereas those with PVE ≥ 1.0% but < 2.0% were considered putative evidence for moderate-effect QTL (n = 35). Identical or proximal lead SNPs associated with ADG, DMI, MMWT, and RFI collectively supported the potential for either pleiotropic QTL, or independent but proximal causal mutations for multiple traits within and between the analyzed populations. Marker-based heritability estimates for all investigated traits ranged from 0.18 to 0.60 using 778K genotypes, or from 0.17 to 0.57 using 50K genotypes (reduced from Illumina 778K HD to Illumina Bovine SNP50). An investigation to determine if QTL detected by 778K analysis could also be detected using 50K genotypes produced variable results, suggesting that 50K analyses were generally insufficient for QTL detection in these populations, and that relevant breeding or selection programs should be based on higher density analyses (imputed or directly ascertained). Fourteen moderate to large-effect QTL regions which ranged from being physically proximal (lead SNPs ≤ 3Mb) to fully overlapping for RFI, DMI, ADG, and MMWT were detected within and between populations, and included evidence for pleiotropy, proximal but independent causal mutations, and multi-breed QTL. Bovine positional candidate genes for these traits were functionally conserved across vertebrate species.

Using DNA methylation profiles ( n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

The importance of the rumen microbiota on nutrient cycling to the animal is well recognized; however, our understanding of the influence of the rumen microbiome composition on feed efficiency is limited. The rumen microbiomes of two large animal cohorts (125 heifers and 122 steers) were characterized to identify specific bacterial members (operational taxonomic units [OTUs]) associated with feed efficiency traits (ADFI, ADG, and G:F) in beef cattle. The heifer and steer cohorts were fed a forage-based diet and a concentrate-based diet, respectively. A rumen sample was obtained from each animal via esophageal tubing and bacterial community composition was determined through 16S rRNA gene sequencing of the V4 region. Based on a regression approach that used individual performance measures, animals were classified into divergent feed efficiency groups. Within cohort, an extreme set of 16 animals from these divergent groups was selected as a discovery population to identify differentially abundant OTUs across the rumen bacterial communities. The remaining samples from each cohort were selected to perform forward stepwise regressions using the differentially abundant OTUs as explanatory variables to distinguish predictive OTUs for the feed efficiency traits and to quantify the OTUs collective impact on feed efficiency phenotypes. OTUs belonging to the families Prevotellaceae and Victivallaceae were present across models for heifers, whereas OTUs belonging to the families Prevotellaceae and Lachnospiraceae were present across models for steers. Within the heifer cohort, models explained 19.3%, 25.3%, and 19.8% of the variation for ADFI, ADG, and G:F, respectively. Within the steer cohort, models explained 27.7%, 32.5%, and 26.9% of the variation for ADFI, ADG, and G:F, respectively. Overall, this study suggests a substantial role of the rumen microbiome on feed efficiency responses.

Major challenges for illuminating the genetic basis of phenotypic evolution are to identify causative mutations, to quantify their functional effects, to trace their origins as new or preexisting variants, and to assess the manner in which segregating variation is transduced into species differences. Here, we report an experimental analysis of genetic variation in hemoglobin (Hb) function within and among species of Peromyscus mice that are native to different elevations. A multilocus survey of sequence variation in the duplicated HBA and HBB genes in Peromyscus maniculatus revealed that function-altering amino acid variants are widely shared among geographically disparate populations from different elevations, and numerous amino acid polymorphisms are also shared with closely related species. Variation in Hb-O₂ affinity within and among populations of P. maniculatus is attributable to numerous amino acid mutations that have individually small effects. One especially surprising feature of the Hb polymorphism in P. maniculatus is that an appreciable fraction of functional standing variation in the two transcriptionally active HBA paralogs is attributable to recurrent gene conversion from a tandemly linked HBA pseudogene. Moreover, transpecific polymorphism in the duplicated HBA genes is not solely attributable to incomplete lineage sorting or introgressive hybridization; instead, it is mainly attributable to recurrent interparalog gene conversion that has occurred independently in different species. Partly as a result of concerted evolution between tandemly duplicated globin genes, the same amino acid changes that contribute to variation in Hb function within P. maniculatus also contribute to divergence in Hb function among different species of Peromyscus. In the case of function-altering Hb mutations in Peromyscus, there is no qualitative or quantitative distinction between segregating variants within species and fixed differences between species.

In light of recent host-microbial association studies, a consensus is evolving that species composition of the gastrointestinal microbiota is a polygenic trait governed by interactions between host genetic factors and the environment. Here, we investigated the effect of host genetic factors in shaping the bacterial species composition in the rumen by performing a genome-wide association study. Using a common set of 61,974 single-nucleotide polymorphisms found in cattle genomes (n = 586) and corresponding rumen bacterial community composition, we identified operational taxonomic units (OTUs), Families and Phyla with high heritability. The top associations (1-Mb windows) were located on 7 chromosomes. These regions were associated with the rumen microbiota in multiple ways; some (chromosome 19; position 3.0–4.0 Mb) are associated with closely related taxa (Prevotellaceae, Paraprevotellaceae, and RF16), some (chromosome 27; position 3.0–4.0 Mb) are associated with distantly related taxa (Prevotellaceae, Fibrobacteraceae, RF16, RFP12, S24-7, Lentisphaerae, and Tenericutes) and others (chromosome 23; position 0.0–1.0) associated with both related and unrelated taxa. The annotated genes associated with identified genomic regions suggest the associations observed are directed toward selective absorption of volatile fatty acids from the rumen to increase energy availability to the host. This study demonstrates that host genetics affects rumen bacterial community composition.