Unveiling recent and ongoing adaptive selection in human populations.

Genome-wide scans for signals of selection have become a routine part of the analysis of population genomic variation datasets and have resulted in compelling evidence of selection during recent human evolution. This Essay spotlights methodological innovations that have enabled the detection of selection over very recent timescales, even in contemporary human populations. By harnessing large-scale genomic and phenotypic datasets, these new methods use different strategies to uncover connections between genotype, phenotype, and fitness. This Essay outlines the rationale and key findings of each strategy, discusses challenges in interpretation, and describes opportunities to improve detection and understanding of ongoing selection in human populations.

Overlooked roles of DNA damage and maternal age in generating human germline mutations.

The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact that there are both more mutations and more cell divisions in the male than in the female germline. When analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that view into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental age. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C-to-G transversions and CpG transitions, which together constitute over one-fourth of all base substitution mutations, show genomic distributions and sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Moreover, we find evidence that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations in the embryo. These findings reveal underappreciated roles of DNA damage and maternal age in the genesis of human germline mutations.

Correction: The population genetics of human disease: The case of recessive, lethal mutations.

[This corrects the article DOI: 10.1371/journal.pgen.1006915.].

Frequent nonallelic gene conversion on the human lineage and its effect on the divergence of gene duplicates.

Gene conversion is the copying of a genetic sequence from a "donor" region to an "acceptor." In nonallelic gene conversion (NAGC), the donor and the acceptor are at distinct genetic loci. Despite the role NAGC plays in various genetic diseases and the concerted evolution of gene families, the parameters that govern NAGC are not well characterized. Here, we survey duplicate gene families and identify converted tracts in 46% of them. These conversions reflect a large GC bias of NAGC. We develop a sequence evolution model that leverages substantially more information in duplicate sequences than used by previous methods and use it to estimate the parameters that govern NAGC in humans: a mean converted tract length of 250 bp and a probability of [Formula: see text] per generation for a nucleotide to be converted (an order of magnitude higher than the point mutation rate). Despite this high baseline rate, we show that NAGC slows down as duplicate sequences diverge-until an eventual "escape" of the sequences from its influence. As a result, NAGC has a small average effect on the sequence divergence of duplicates. This work improves our understanding of the NAGC mechanism and the role that it plays in the evolution of gene duplicates.

The population genetics of human disease: The case of recessive, lethal mutations.

Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in this study. Beyond the specific application, this study highlights the parameters likely to be important in shaping the frequencies of Mendelian disease alleles.

Human Germline Mutation and the Erratic Evolutionary Clock.

Our understanding of the chronology of human evolution relies on the "molecular clock" provided by the steady accumulation of substitutions on an evolutionary lineage. Recent analyses of human pedigrees have called this understanding into question by revealing unexpectedly low germline mutation rates, which imply that substitutions accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. We dissect the steps involved, emphasizing that dating evolutionary events requires not "a mutation rate" but a precise characterization of how mutations accumulate in development in males and females-knowledge that remains elusive.

Interpreting the Dependence of Mutation Rates on Age and Time.

Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understanding how mutation rates depend on sex, age, and cell division rate. We show that the accrual of mutations should track cell divisions not only when mutations are replicative in origin but also when they are non-replicative and repaired efficiently. One implication is that observations from diverse fields that to date have been interpreted as pointing to a replicative origin of most mutations could instead reflect the accumulation of mutations arising from endogenous reactions or exogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, unless life history traits co-vary, the phylogenetic "molecular clock" should not be expected to run steadily across species.

Ancestry runs deeper than blood: the evolutionary history of ABO points to cryptic variation of functional importance.

The ABO histo-blood group, first discovered over a century ago, is found not only in humans but also in many other primate species, with the same genetic variants maintained for at least 20 million years. Polymorphisms in ABO have been associated with susceptibility to a large number of human diseases, from gastric cancers to immune or artery diseases, but the adaptive phenotypes to which the polymorphism contributes remain unclear. We suggest that variation in ABO has been maintained by frequency-dependent or fluctuating selection pressures, potentially arising from co-evolution with gut pathogens. We further hypothesize that the histo-blood group labels A, B, AB, and O do not offer a full description of variants maintained by natural selection, implying that there are unrecognized, functionally important, antigens beyond the ABO group in humans and other primates.

Stable population structure in Europe since the Iron Age, despite high mobility.

Ancient DNA research in the past decade has revealed that European population structure changed dramatically in the prehistoric period (14,000-3000 years before present, YBP), reflecting the widespread introduction of Neolithic farmer and Bronze Age Steppe ancestries. However, little is known about how population structure changed from the historical period onward (3000 YBP - present). To address this, we collected whole genomes from 204 individuals from Europe and the Mediterranean, many of which are the first historical period genomes from their region (e.g. Armenia and France). We found that most regions show remarkable inter-individual heterogeneity. At least 7% of historical individuals carry ancestry uncommon in the region where they were sampled, some indicating cross-Mediterranean contacts. Despite this high level of mobility, overall population structure across western Eurasia is relatively stable through the historical period up to the present, mirroring geography. We show that, under standard population genetics models with local panmixia, the observed level of dispersal would lead to a collapse of population structure. Persistent population structure thus suggests a lower effective migration rate than indicated by the observed dispersal. We hypothesize that this phenomenon can be explained by extensive transient dispersal arising from drastically improved transportation networks and the Roman Empire's mobilization of people for trade, labor, and military. This work highlights the utility of ancient DNA in elucidating finer scale human population dynamics in recent history.

Limited role of generation time changes in driving the evolution of the mutation spectrum in humans.

Recent studies have suggested that the human germline mutation rate and spectrum evolve rapidly. Variation in generation time has been linked to these changes, though its contribution remains unclear. We develop a framework to characterize temporal changes in polymorphisms within and between populations, while controlling for the effects of natural selection and biased gene conversion. Application to the 1000 Genomes Project dataset reveals multiple independent changes that arose after the split of continental groups, including a previously reported, transient elevation in TCC>TTC mutations in Europeans and novel signals of divergence in C>Gand T>A mutation rates among population samples. We also find a significant difference between groups sampled in and outside of Africa in old T>C polymorphisms that predate the out-of-Africa migration. This surprising signal is driven by TpG>CpG mutations and stems in part from mis-polarized CpG transitions, which are more likely to undergo recurrent mutations. Finally, by relating the mutation spectrum of polymorphisms to parental age effects on de novo mutations, we show that plausible changes in the generation time cannot explain the patterns observed for different mutation types jointly. Thus, other factors - genetic modifiers or environmental exposures - must have had a non-negligible impact on the human mutation landscape.

Each human has 23 pairs of chromosomes, one set inherited from each parent. But the child's chromosomes are not an exact copy of their parents' chromosomes. Spontaneous changes or mutations in the DNA during the formation of the egg or sperm cells, or early development of the embryo, can change a small fraction of the nucleotides or 'letters' that make up the DNA. These modifications are an important source of genetic diversity in human populations and contribute to the evolution of new traits. Each genetic variant in present-day human populations represents a mutation in one of their ancestors. The types and frequencies of variants vary across human populations and have changed over time, suggesting that mutation patterns have evolved in the past. But the processes driving these population-level differences remain elusive. One possible factor may be changes in the average age of reproduction or the generation time in a population . For example, older parents contribute more ­ and also different types of ­ new mutations to their children than younger parents do. Populations, where it is customary to have children at older ages, may therefore have a different mutation landscape. To find out if this is indeed the case, Gao et al. used computer algorithms to analyze the genomes of hundreds of people living on three continents who participated in 'the 1,000 Genomes Project'. The analysis identified differences in mutation patterns across continental groups and estimated when these changes occurred. Further, they showed that although the age of reproduction had an impact on the mutation landscape, differences in generation time alone could not explain the observed changes in the human mutation spectrum. Factors other than generation time, such as environmental exposures, may have played a role in shifting these patterns. The study provides new insights into the changes in the mutation landscape over the course of human evolution. Mapping these patterns in humans worldwide may help scientists understand the causes underlying these changes. The techniques used by Gao et al. may also help analyze changes in mutation patterns in other organisms.

A genetic history of continuity and mobility in the Iron Age central Mediterranean.

The Iron Age was a dynamic period in central Mediterranean history, with the expansion of Greek and Phoenician colonies and the growth of Carthage into the dominant maritime power of the Mediterranean. These events were facilitated by the ease of long-distance travel following major advances in seafaring. We know from the archaeological record that trade goods and materials were moving across great distances in unprecedented quantities, but it is unclear how these patterns correlate with human mobility. Here, to investigate population mobility and interactions directly, we sequenced the genomes of 30 ancient individuals from coastal cities around the central Mediterranean, in Tunisia, Sardinia and central Italy. We observe a meaningful contribution of autochthonous populations, as well as highly heterogeneous ancestry including many individuals with non-local ancestries from other parts of the Mediterranean region. These results highlight both the role of local populations and the extreme interconnectedness of populations in the Iron Age Mediterranean. By studying these trans-Mediterranean neighbours together, we explore the complex interplay between local continuity and mobility that shaped the Iron Age societies of the central Mediterranean.

The Arabidopsis gene hypersensitive to phosphate starvation 3 encodes ethylene overproduction 1.

When plants are subjected to a deficiency in inorganic phosphate (Pi), they exhibit an array of responses to cope with this nutritional stress. In this work, we have characterized two Arabidopsis mutants, hps3-1 and hps3-2 (hypersensitive to Pi starvation 3), that have altered expression of Pi starvation-induced (PSI) genes and enhanced production of acid phosphatase (APase) when grown under either Pi sufficiency or deficiency conditions. hps3-1 and hps3-2, however, accumulate less anthocyanin than the wild type when grown on a Pi-deficient medium. Molecular cloning indicated that the phenotypes of hps3 mutants were caused by mutations within the ETO1 (ETHYLENE OVERPRODUCTION 1) gene. In Arabidopsis, ETO1 encodes a negative regulator of ethylene biosynthesis, and mutation of ETO1 causes Arabidopsis seedlings to overproduce ethylene. The ethylene biosynthesis inhibitor aminoethoxyvinyl glycine or the ethylene perception inhibitor Ag(+) suppressed all the mutant phenotypes of hps3. Taken together, these results provide further genetic evidence that ethylene is an important regulator of multiple plant responses to Pi starvation. Furthermore, we found that a change in ethylene level has differential effects on the expression of PSI genes, maintenance of Pi homeostasis, production of APase and accumulation of anthocyanin. We also demonstrated that ethylene signaling mainly regulates the activity of root surface-associated APases rather than total APase activity.

Evidence for Weak Selective Constraint on Human Gene Expression.

Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression. Here, we explore the effects of stabilizing selection on cis-regulatory genetic variation in humans. We analyze patterns of expression variation at copy number variants and find evidence for selection against large increases in gene expression. Using allele-specific expression (ASE) data, we further show evidence of selection against smaller-effect variants. We estimate that, across all genes, singletons in a sample of 122 individuals have ∼2.2× greater effects on expression variation than the average variant across allele frequencies. Despite their increased effect size relative to common variants, we estimate that singletons in the sample studied explain, on average, only 5% of the heritability of gene expression from cis-regulatory variants. Finally, we show that genes depleted for loss-of-function variants are also depleted for cis-eQTLs and have low levels of allelic imbalance, confirming tighter constraint on the expression levels of these genes. We conclude that constraint on gene expression is present, but has relatively weak effects on most cis-regulatory variants, thus permitting high levels of gene-regulatory genetic variation.

Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation.

The number of de novo mutations (DNMs) found in an offspring's genome increases with both paternal and maternal age. But does the rate of mutation accumulation in human gametes differ across families? Using sequencing data from 33 large, three-generation CEPH families, we observed significant variability in parental age effects on DNM counts across families, ranging from 0.19 to 3.24 DNMs per year. Additionally, we found that ~3% of DNMs originated following primordial germ cell specification in a parent, and differed from non-mosaic germline DNMs in their mutational spectra. We also discovered that nearly 10% of candidate DNMs in the second generation were post-zygotic, and present in both somatic and germ cells; these gonosomal mutations occurred at equivalent frequencies on both parental haplotypes. Our results demonstrate that rates of germline mutation accumulation vary among families with similar ancestry, and confirm that post-zygotic mosaicism is a substantial source of human DNM.

Landscape of stimulation-responsive chromatin across diverse human immune cells.

A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Allele-specific read mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need to characterize the effects of genetic variation in stimulated cells.

Ancient Rome: A genetic crossroads of Europe and the Mediterranean.

Ancient Rome was the capital of an empire of ~70 million inhabitants, but little is known about the genetics of ancient Romans. Here we present 127 genomes from 29 archaeological sites in and around Rome, spanning the past 12,000 years. We observe two major prehistoric ancestry transitions: one with the introduction of farming and another prior to the Iron Age. By the founding of Rome, the genetic composition of the region approximated that of modern Mediterranean populations. During the Imperial period, Rome's population received net immigration from the Near East, followed by an increase in genetic contributions from Europe. These ancestry shifts mirrored the geopolitical affiliations of Rome and were accompanied by marked interindividual diversity, reflecting gene flow from across the Mediterranean, Europe, and North Africa.

Insight into the Role of Surface Wettability in Electrocatalytic Hydrogen Evolution Reactions Using Light-Sensitive Nanotubular TiO2 Supported Pt Electrodes.

Surface wettability is of importance for electrochemical reactions. Herein, its role in electrochemical hydrogen evolution reactions is investigated using light-sensitive nanotubular TiO2 supported Pt as hydrogen evolution electrodes (HEEs). The HEEs are fabricated by photocatalytic deposition of Pt particles on TiO2 nanotubes followed by hydrophobization with vaporized octadecyltrimethoxysilane (OTS) molecules. The surface wettability of HEEs is subsequently regulated in situ from hydrophobicity to hydrophilicity by photocatalytic decomposition of OTS molecules using ultraviolet light. It is found that hydrophilic HEEs demonstrate a larger electrochemical active area of Pt and a lower adhesion force to a gas bubble when compared with hydrophobic ones. The former allows more protons to react on the electrode surface at small overpotential so that a larger current is produced. The latter leads to a quick release of hydrogen gas bubbles from the electrode surface at large overpotential, which ensures the contact between catalysts and electrolyte. These two characteristics make hydrophilic HEEs generate a much high current density for HERs. Our results imply that the optimization of surface wettability is of significance for improving the electrocatalytic activity of HEEs.

Detection of human adaptation during the past 2000 years.

Detection of recent natural selection is a challenging problem in population genetics. Here we introduce the singleton density score (SDS), a method to infer very recent changes in allele frequencies from contemporary genome sequences. Applied to data from the UK10K Project, SDS reflects allele frequency changes in the ancestors of modern Britons during the past ~2000 to 3000 years. We see strong signals of selection at lactase and the major histocompatibility complex, and in favor of blond hair and blue eyes. For polygenic adaptation, we find that recent selection for increased height has driven allele frequency shifts across most of the genome. Moreover, we identify shifts associated with other complex traits, suggesting that polygenic adaptation has played a pervasive role in shaping genotypic and phenotypic variation in modern humans.

Footprints of ancient-balanced polymorphisms in genetic variation data from closely related species.

When long-lasting, balancing selection can lead to "trans-species" polymorphisms that are shared by two or more species identical by descent. In such cases, the gene genealogy at the selected site clusters by allele instead of by species, and nearby neutral sites also have unusual genealogies because of linkage. While this scenario is expected to leave discernible footprints in genetic variation data, the specific patterns remain poorly characterized. Motivated by recent findings in primates, we focus on the case of a biallelic polymorphism under ancient balancing selection and derive approximations for summaries of the polymorphism data from two species. Specifically, we characterize the length of the segment that carries most of the footprints, the expected number of shared neutral single nucleotide polymorphisms (SNPs), and the patterns of allelic associations among them. We confirm the accuracy of our approximations by coalescent simulations. We further show that for humans and chimpanzees-more generally, for pairs of species with low genetic diversity levels-these patterns are highly unlikely to be generated by neutral recurrent mutations. We discuss the implications for the design and interpretation of genome scans for ancient balanced polymorphisms in primates and other taxa.

An estimate of the average number of recessive lethal mutations carried by humans.

The effects of inbreeding on human health depend critically on the number and severity of recessive, deleterious mutations carried by individuals. In humans, existing estimates of these quantities are based on comparisons between consanguineous and nonconsanguineous couples, an approach that confounds socioeconomic and genetic effects of inbreeding. To overcome this limitation, we focused on a founder population that practices a communal lifestyle, for which there is almost complete Mendelian disease ascertainment and a known pedigree. Focusing on recessive lethal diseases and simulating allele transmissions, we estimated that each haploid set of human autosomes carries on average 0.29 (95% credible interval [0.10, 0.84]) recessive alleles that lead to complete sterility or death by reproductive age when homozygous. Comparison to existing estimates in humans suggests that a substantial fraction of the total burden imposed by recessive deleterious variants is due to single mutations that lead to sterility or death between birth and reproductive age. In turn, comparison to estimates from other eukaryotes points to a surprising constancy of the average number of recessive lethal mutations across organisms with markedly different genome sizes.