Events in primate evolution are often dated by assuming a constant rate of substitution per unit time, but the validity of this assumption remains unclear. Among mammals, it is well known that there exists substantial variation in yearly substitution rates. Such variation is to be expected from differences in life history traits, suggesting it should also be found among primates. Motivated by these considerations, we analyze whole genomes from 10 primate species, including Old World Monkeys (OWMs), New World Monkeys (NWMs), and apes, focusing on putatively neutral autosomal sites and controlling for possible effects of biased gene conversion and methylation at CpG sites. We find that substitution rates are up to 64% higher in lineages leading from the hominoid-NWM ancestor to NWMs than to apes. Within apes, rates are ∼2% higher in chimpanzees and ∼7% higher in the gorilla than in humans. Substitution types subject to biased gene conversion show no more variation among species than those not subject to it. Not all mutation types behave similarly, however; in particular, transitions at CpG sites exhibit a more clocklike behavior than do other types, presumably because of their nonreplicative origin. Thus, not only the total rate, but also the mutational spectrum, varies among primates. This finding suggests that events in primate evolution are most reliably dated using CpG transitions. Taking this approach, we estimate the human and chimpanzee divergence time is 12.1 million years, and the human and gorilla divergence time is 15.1 million years. molecular clock | mutation rate | primate evolution | CpG transition rate | human-ape divergence time G ermline mutations are the ultimate source of genetic differences among individuals and species. They are thought to arise from a combination of errors in DNA replication (e.g., the chance misincorporation of a base pair) or damage that is unrepaired by the time of replication (e.g., the spontaneous deamination of methylated CpG sites) (1). If mutations are neutral (i.e., do not affect fitness), then the rate at which they arise will be equal to the substitution rate (2). A key consequence is that if mutation rates remain constant over time, substitution rates should likewise be constant.This assumption of constancy of substitution rates plays a fundamental role in evolutionary genetics by providing a molecular clock with which to date events inferred from genetic data (3). Notably, important events in human evolution for which there is no fossil record (e.g., when humans and chimpanzees split, or when anatomically modern humans left Africa) are dated using a mutation rate obtained from contemporary pedigrees or phylogenetic analysis, assuming the per year rate has remained unchanged for millions of years (4).However, we know from studies of mammalian phylogenies, as well as of other taxa, that there can be substantial variation in substitution rates per unit time (5-7). In particular, there is the well-known hypothesis of a "generation time effect" on substitution rates,...

Despite centuries of research, much about the barbarian migrations that took place between the fourth and sixth centuries in Europe remains hotly debated. To better understand this key era that marks the dawn of modern European societies, we obtained ancient genomic DNA from 63 samples from two cemeteries (from Hungary and Northern Italy) that have been previously associated with the Longobards, a barbarian people that ruled large parts of Italy for over 200 years after invading from Pannonia in 568 CE. Our dense cemetery-based sampling revealed that each cemetery was primarily organized around one large pedigree, suggesting that biological relationships played an important role in these early medieval societies. Moreover, we identified genetic structure in each cemetery involving at least two groups with different ancestry that were very distinct in terms of their funerary customs. Finally, our data are consistent with the proposed long-distance migration from Pannonia to Northern Italy.

When humans moved from Asia toward the Americas over 18,000 y ago and eventually peopled the New World they encountered a new environment with extreme climate conditions and distinct dietary resources. These environmental and dietary pressures may have led to instances of genetic adaptation with the potential to influence the phenotypic variation in extant Native American populations. An example of such an event is the evolution of the fatty acid desaturases (FADS) genes, which have been claimed to harbor signals of positive selection in Inuit populations due to adaptation to the cold Greenland Arctic climate and to a protein-rich diet. Because there was evidence of intercontinental variation in this genetic region, with indications of positive selection for its variants, we decided to compare the Inuit findings with other Native American data. Here, we use several lines of evidence to show that the signal of FADS-positive selection is not restricted to the Arctic but instead is broadly observed throughout the Americas. The shared signature of selection among populations living in such a diverse range of environments is likely due to a single and strong instance of local adaptation that took place in the common ancestral population before their entrance into the New World. These first Americans peopled the whole continent and spread this adaptive variant across a diverse set of environments.

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.

Despite centuries of research, much about the barbarian migrations that took place between the fourth and sixth centuries in Europe remains hotly debated. To better understand this key era that marks the dawn of modern European societies, we obtained ancient genomic DNA from 63 samples from two cemeteries (from Hungary and Northern Italy) that have been previously associated with the Longobards , a barbarian people that ruled large parts of Italy for over 200 years after invading from Pannonia in 568 CE. Our dense cemetery-based sampling revealed that each cemetery was primarily organized around one large pedigree, suggesting that biological relationships played an important role in these early Medieval societies. Moreover, we identified genetic structure in each cemetery involving at least two groups with different ancestry that were very distinct in terms of their funerary customs.Finally, our data was consistent with the proposed long-distance migration from Pannonia to Northern Italy.

Culture and genetics rely on two distinct but not isolated transmission systems. Cultural processes may change the human selective environment and thereby affect which individuals survive and reproduce. Here, we evaluated whether the modes of subsistence in Native American populations and the frequencies of the ABCA1*Arg230Cys polymorphism were correlated. Further, we examined whether the evolutionary consequences of the agriculturally constructed niche in Mesoamerica could be considered as a gene-culture coevolution model. For this purpose, we genotyped 229 individuals affiliated with 19 Native American populations and added data for 41 other Native American groups (n = 1905) to the analysis. In combination with the SNP cluster of a neutral region, this dataset was then used to unravel the scenario involved in 230Cys evolutionary history. The estimated age of 230Cys is compatible with its origin occurring in the American continent. The correlation of its frequencies with the archeological data on Zea pollen in Mesoamerica/Central America, the neutral coalescent simulations, and the FST-based natural selection analysis suggest that maize domestication was the driving force in the increase in the frequencies of 230Cys in this region. These results may represent the first example of a gene-culture coevolution involving an autochthonous American allele.

Highlights d Bronze Age (BA) Helladic, Cycladic, and Minoan genomes from the Aegean were sequenced d 3,000 BCE Aegeans are homogeneous and derive ancestry mainly from Neolithic farmers d Neolithic Caucasus-like and BA Pontic-Caspian Steppe-like gene flow shaped the Aegean d Present-day Greeks are genetically similar to 2,000 BCE Aegeans from Northern Greece

Events in primate evolution are often dated by assuming a constant rate of substitution per unit time, but the validity of this assumption remains unclear. Among mammals, it is well known that there exists substantial variation in yearly substitution rates. Such variation is to be expected from differences in life history traits, suggesting it should also be found among primates. Motivated by these considerations, we analyze whole genomes from 10 primate species, including Old World Monkeys (OWMs), New World Monkeys (NWMs), and apes, focusing on putatively neutral autosomal sites and controlling for possible effects of biased gene conversion and methylation at CpG sites. We find that substitution rates are up to 64% higher in lineages leading from the hominoid-NWM ancestor to NWMs than to apes. Within apes, rates are ∼2% higher in chimpanzees and ∼7% higher in the gorilla than in humans. Substitution types subject to biased gene conversion show no more variation among species than those not subject to it. Not all mutation types behave similarly, however; in particular, transitions at CpG sites exhibit a more clocklike behavior than do other types, presumably because of their nonreplicative origin. Thus, not only the total rate, but also the mutational spectrum, varies among primates. This finding suggests that events in primate evolution are most reliably dated using CpG transitions. Taking this approach, we estimate the human and chimpanzee divergence time is 12.1 million years, and the human and gorilla divergence time is 15.1 million years. molecular clock | mutation rate | primate evolution | CpG transition rate | human-ape divergence time G ermline mutations are the ultimate source of genetic differences among individuals and species. They are thought to arise from a combination of errors in DNA replication (e.g., the chance misincorporation of a base pair) or damage that is unrepaired by the time of replication (e.g., the spontaneous deamination of methylated CpG sites) (1). If mutations are neutral (i.e., do not affect fitness), then the rate at which they arise will be equal to the substitution rate (2). A key consequence is that if mutation rates remain constant over time, substitution rates should likewise be constant.This assumption of constancy of substitution rates plays a fundamental role in evolutionary genetics by providing a molecular clock with which to date events inferred from genetic data (3). Notably, important events in human evolution for which there is no fossil record (e.g., when humans and chimpanzees split, or when anatomically modern humans left Africa) are dated using a mutation rate obtained from contemporary pedigrees or phylogenetic analysis, assuming the per year rate has remained unchanged for millions of years (4).However, we know from studies of mammalian phylogenies, as well as of other taxa, that there can be substantial variation in substitution rates per unit time (5-7). In particular, there is the well-known hypothesis of a "generation time effect" on substitution rates,...