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Approximately 2–4% of genetic material in human populations outside Africa is derived from Neanderthals who interbred with anatomically modern humans. Recent studies have shown that this Neanderthal DNA is depleted around functional genomic regions; this has been suggested to be a consequence of harmful epistatic interactions between human and Neanderthal alleles. However, using published estimates of Neanderthal inbreeding and the distribution of mutational fitness effects, we infer that Neanderthals had at least 40% lower fitness than humans on average; this increased load predicts the reduction in Neanderthal introgression around genes without the need to invoke epistasis. We also predict a residual Neanderthal mutational load in non-Africans, leading to a fitness reduction of at least 0.5%. This effect of Neanderthal admixture has been left out of previous debate on mutation load differences between Africans and non-Africans. We also show that if many deleterious mutations are recessive, the Neanderthal admixture fraction could increase over time due to the protective effect of Neanderthal haplotypes against deleterious alleles that arose recently in the human population. This might partially explain why so many organisms retain gene flow from other species and appear to derive adaptive benefits from introgression.

Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed “next‐generation clock” DNAmGrimAge outperforms “first‐generation clocks” in predicting longevity and the onset of many age‐related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm‐based biomarker of healthy aging. A fundamental biological property of epigenetic, and in particular DNAm modifications, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the “Diet, Physical Activity, and Mammography” (DAMA) study: a 24‐month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial. Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer‐related pathways. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging‐related epigenetic mechanisms. In a 24‐month randomized factorial intervention trial, dietary and physical activity interventions slowed down DNA methylation‐based biomarkers of aging.

Populations with higher genetic diversity and larger effective sizes have greater evolutionary capacity (i.e., adaptive potential) to respond to ecological stressors. We are interested in how the variation captured in protein‐coding genes fluctuates relative to overall genomic diversity and whether smaller populations suffer greater costs due to their genetic load of deleterious mutations compared with larger populations. We analyzed individual whole‐genome sequences (N = 74) from three different populations of Montezuma quail (Cyrtonyx montezumae), a small ground‐dwelling bird that is sustainably harvested in some portions of its range but is of conservation concern elsewhere. Our historical demographic results indicate that Montezuma quail populations in the United States exhibit low levels of genomic diversity due in large part to long‐term declines in effective population sizes over nearly a million years. The smaller and more isolated Texas population is significantly more inbred than the large Arizona and the intermediate‐sized New Mexico populations we surveyed. The Texas gene pool has a significantly smaller proportion of strongly deleterious variants segregating in the population compared with the larger Arizona gene pool. Our results demonstrate that even in small populations, highly deleterious mutations are effectively purged and/or lost due to drift. However, we find that in small populations the realized genetic load is elevated because of inbreeding coupled with a higher frequency of slightly deleterious mutations that are manifested in homozygotes. Overall, our study illustrates how population genomics can be used to proactively assess both neutral and functional aspects of contemporary genetic diversity in a conservation framework while simultaneously considering deeper demographic histories.

Habitat loss and population fragmentation pose severe threats to biodiversity and the survival of many species. Population isolation and the decline in effective population size lead to increased genetic drift and inbreeding. In turn, this reduces neutral diversity, and it also affects the genetic load of deleterious mutations. Here, we analyse the effect of such genomic erosion by designing a spatially explicit, individual based model in SLiM, simulating the effects of the recorded habitat loss in Mauritius over the past ~ 250 years. We show that the loss of neutral diversity (genome-wide heterozygosity) was barely noticeable during the first 100 years of habitat loss. Changes to the genetic load took even more time to register, and they only became apparent circa 200 years after the start of habitat decline. Although a considerable number of deleterious mutations were lost by drift, others increased in frequency. The masked load was thus converted into a realised load, which compromised individual fitness and population viability after much of the native habitat had been lost. Importantly, genomic erosion continued after the metapopulation had stabilised at low numbers. Our study shows that historic habitat loss can pose a sustained threat to populations also in future generations, even without further habitat loss. The UN’s Decade on Ecosystem Restoration needs to lead to transformative change to save species from future extinction, and this requires the urgent restoration of natural habitats.

Expanding populations incur a mutation burden, the so-called expansion load. Using a mixture of individual-based simulations and analytical modeling, we study the expansion load process in models where population growth depends on the population’s fitness (i.e., hard selection). We show that expansion load can severely slow down expansions and limit a species’ range, even in the absence of environmental variation. We also study the effect of recombination on the dynamics of a species range and on the evolution of mean fitness on the wave front. If recombination is strong, mean fitness on front approaches an equilibrium value at which the effects of fixed mutations cancel each other out. The equilibrium rate at which new demes are colonized is similar to the rate at which beneficial mutations spread through the core. Without recombination, the dynamics is more complex, and beneficial mutations from the core of the range can invade the front of the expansion, which results in irregular and episodic expansion. Although the rate of adaptation is generally higher in recombining organisms, the mean fitness on the front may be larger in the absence of recombination because high-fitness individuals from the core have a higher chance to invade the front. Our findings have important consequences for the evolutionary dynamics of species ranges as well as on the role and the evolution of recombination during range expansions.

PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma.

Recent theoretical work suggested that deleterious mutations could accumulate during the range expansion of a species, negatively affecting its fitness. Recent theory predicts that the fitness of pioneer populations can decline when species expand their range, due to high rates of genetic drift on wave fronts making selection less efficient at purging deleterious variants. To test these predictions, we studied the fate of mutator bacteria expanding their range for 1650 generations on agar plates. In agreement with theory, we find that growth abilities of strains with a high mutation rate (HMR lines) decreased significantly over time, unlike strains with a lower mutation rate (LMR lines) that present three to four times fewer mutations. Estimation of the distribution of fitness effect under a spatially explicit model reveals a mean negative effect for new mutations (−0.38%), but it suggests that both advantageous and deleterious mutations have accumulated during the experiment. Furthermore, the fitness of HMR lines measured in different environments has decreased relative to the ancestor strain, whereas that of LMR lines remained unchanged. Contrastingly, strains with a HMR evolving in a well-mixed environment accumulated less mutations than agar-evolved strains and showed an increased fitness relative to the ancestor. Our results suggest that spatially expanding species are affected by deleterious mutations, leading to a drastic impairment of their evolutionary potential.

Genetic drift is an important evolutionary force of strength inversely proportional to Ne, the effective population size. The impact of drift on genome diversity and evolution is known to vary among species, but quantifying this effect is a difficult task. Here we assess the magnitude of variation in drift power among species of animals via its effect on the mutation load - which implies also inferring the distribution of fitness effects of deleterious mutations. To this aim, we analyze the nonsynonymous (amino-acid changing) and synonymous (amino-acid conservative) allele frequency spectra in a large sample of metazoan species, with a focus on the primates vs. fruit flies contrast. We show that a Gamma model of the distribution of fitness effects is not suitable due to strong differences in estimated shape parameters among taxa, while adding a class of lethal mutations essentially solves the problem. Using the Gamma + lethal model and assuming that the mean deleterious effects of nonsynonymous mutations is shared among species, we estimate that the power of drift varies by a factor of at least 500 between large-Ne and small-Ne species of animals, i.e., an order of magnitude more than the among-species variation in genetic diversity. Our results are relevant to Lewontin's paradox while further questioning the meaning of the Ne parameter in population genomics.

Transitions to captivity often produce population bottlenecks. On the one hand, bottlenecks increase inbreeding and decrease effective population size, thus increasing extinction risk. On the other hand, elevated homozygosity associated with inbreeding may purge deleterious mutations. Previous empirical studies of purging in captive breeding programs have focused on phenotypic measurements. We test natural selection's ability to purge deleterious mutations following an extreme population bottleneck by analyzing patterns of genetic diversity in wild and captive-bred individuals of the Lord Howe Island stick insect, Dryococelus australis. Dryococelus australis has been bred in captivity for two decades, having passed through an extreme bottleneck—only two mating pairs with few new additions since then. The magnitude of the bottleneck together with high female fecundity but low offspring recruitment set up nearly ideal conditions for the purging of deleterious mutations. As expected, captive-bred individuals had a greater number of long runs of homozygosity compared with wild individuals, implying strong inbreeding in captivity which would facilitate purging in homozygous regions. Stop-codon mutations were preferentially depleted in captivity compared with other mutations in coding and noncoding regions. The more deleterious a mutation was predicted to be, the more likely it was found outside of runs of homozygosity, implying that inbreeding facilitates the expression and thus removal of deleterious mutations, even after such an extreme bottleneck and under the benign conditions of captivity. These data implicate inbreeding and recessive deleterious mutation load in fitness variation among captive and wild D. australis.

Background Checkpoint blockade immunotherapy has improved metastatic cancer patient survival, but response rates remain low. There is an unmet need to identify mechanisms and tools to circumvent resistance. In human patients, responses to checkpoint blockade therapy correlate with tumor mutation load, and intrinsic resistance associates with pre-treatment signatures of epithelial mesenchymal transition (EMT), immunosuppression, macrophage chemotaxis and TGF[beta] signaling. Methods To facilitate studies on mechanisms of squamous cell carcinoma (SCC) evasion of checkpoint blockade immunotherapy, we sought to develop a novel panel of murine syngeneic SCC lines reflecting the heterogeneity of human cancer and its responses to immunotherapy. We characterized six Kras-driven cutaneous SCC lines with a range of mutation loads. Following implantation into syngeneic FVB mice, we examined multiple tumor responses to [alpha]-PD-1, [alpha]-TGF[beta] or combinatorial therapy, including tumor growth rate and regression, tumor immune cell composition, acquired tumor immunity, and the role of cytotoxic T cells and Tregs in immunotherapy responses. Results We show that [alpha]-PD-1 therapy is ineffective in establishing complete regression (CR) of tumors in all six SCC lines, but causes partial tumor growth inhibition of two lines with the highest mutations loads, CCK168 and CCK169. [alpha]-TGF[beta] monotherapy results in 20% CR and 10% CR of established CCK168 and CCK169 tumors respectively, together with acquisition of long-term anti-tumor immunity. [alpha]-PD-1 synergizes with [alpha]-TGF[beta], increasing CR rates to 60% (CCK168) and 20% (CCK169). [alpha]-PD-1 therapy enhances CD4 + Treg/CD4 + Th ratios and increases tumor cell pSmad3 expression in CCK168 SCCs, whereas [alpha]-TGF[beta] antibody administration attenuates these effects. We show that [alpha]-TGF[beta] acts in part through suppressing immunosuppressive Tregs induced by [alpha]-PD-1, that limit the anti-tumor activity of [alpha]-PD-1 monotherapy. Additionally, in vitro and in vivo, [alpha]-TGF[beta] acts directly on the tumor cell to attenuate EMT, to activate a program of gene expression that stimulates immuno-surveillance, including up regulation of genes encoding the tumor cell antigen presentation machinery. Conclusions We show that [alpha]-PD-1 not only initiates a tumor rejection program, but can induce a competing TGF[beta]-driven immuno-suppressive program. We identify new opportunities for [alpha]-PD-1/[alpha]-TGF[beta] combinatorial treatment of SCCs especially those with a high mutation load, high CD4+ T cell content and pSmad3 signaling. Our data form the basis for clinical trial of [alpha]-TGF[beta]/[alpha]-PD-1 combination therapy (NCT02947165). Keywords: Checkpoint blockade, Squamous cell carcinoma, Tumor mutation load, [alpha]-TGF[beta] /[alpha]-PD-1 combinatorial immunotherapy, Tregs, pSmad signaling, Epithelial mesenchymal transition (EMT)