There is currently no calibration available for the whole human mtDNA genome, incorporating both coding and control regions. Furthermore, as several authors have pointed out recently, linear molecular clocks that incorporate selectable characters are in any case problematic. We here confirm a modest effect of purifying selection on the mtDNA coding region and propose an improved molecular clock for dating human mtDNA, based on a worldwide phylogeny of > 2000 complete mtDNA genomes and calibrating against recent evidence for the divergence time of humans and chimpanzees. We focus on a time-dependent mutation rate based on the entire mtDNA genome and supported by a neutral clock based on synonymous mutations alone. We show that the corrected rate is further corroborated by archaeological dating for the settlement of the Canary Islands and Remote Oceania and also, given certain phylogeographic assumptions, by the timing of the first modern human settlement of Europe and resettlement after the Last Glacial Maximum. The corrected rate yields an age of modern human expansion in the Americas at approximately 15 kya that-unlike the uncorrected clock-matches the archaeological evidence, but continues to indicate an out-of-Africa dispersal at around 55-70 kya, 5-20 ky before any clear archaeological record, suggesting the need for archaeological research efforts focusing on this time window. We also present improved rates for the mtDNA control region, and the first comprehensive estimates of positional mutation rates for human mtDNA, which are essential for defining mutation models in phylogenetic analyses.

Next-generation sequencing technologies have revolutionized the field of paleogenomics, allowing the reconstruction of complete ancient genomes and their comparison with modern references. However, this requires the processing of vast amounts of data and involves a large number of steps that use a variety of computational tools. Here we present PALEOMIX (http://geogenetics.ku.dk/publications/paleomix), a flexible and user-friendly pipeline applicable to both modern and ancient genomes, which largely automates the in silico analyses behind whole-genome resequencing. Starting with next-generation sequencing reads, PALEOMIX carries out adapter removal, mapping against reference genomes, PCR duplicate removal, characterization of and compensation for postmortem damage, SNP calling and maximum-likelihood phylogenomic inference, and it profiles the metagenomic contents of the samples. As such, PALEOMIX allows for a series of potential applications in paleogenomics, comparative genomics and metagenomics. Applying the PALEOMIX pipeline to the three ancient and seven modern Phytophthora infestans genomes as described here takes 5 d using a 16-core server.

The domestication of the horse ∼5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse domestication are difficult to reconstruct, given the near extinction of wild horses. We therefore sequenced two ancient horse genomes from Taymyr, Russia (at 7.4-and 24.3-fold coverage), both predating the earliest archeological evidence of domestication. We compared these genomes with genomes of domesticated horses and the wild Przewalski's horse and found genetic structure within Eurasia in the Late Pleistocene, with the ancient population contributing significantly to the genetic variation of domesticated breeds. We furthermore identified a conservative set of 125 potential domestication targets using four complementary scans for genes that have undergone positive selection. One group of genes is involved in muscular and limb development, articular junctions, and the cardiac system, and may represent physiological adaptations to human utilization. A second group consists of genes with cognitive functions, including social behavior, learning capabilities, fear response, and agreeableness, which may have been key for taming horses. We also found that domestication is associated with inbreeding and an excess of deleterious mutations. This genetic load is in line with the "cost of domestication" hypothesis also reported for rice, tomatoes, and dogs, and it is generally attributed to the relaxation of purifying selection resulting from the strong demographic bottlenecks accompanying domestication. Our work demonstrates the power of ancient genomes to reconstruct the complex genetic changes that transformed wild animals into their domesticated forms, and the population context in which this process took place.ancient DNA | horse domestication | Przewalski's horse | positive selection | cost of domestication T he domestication of the horse had a far-reaching impact on the sociopolitical and economic trajectories of human societies (1). It not only provided meat and milk (2) but also enabled the development of continent-sized nomadic empires, by transforming warfare and allowing for the rapid spread of goods and information over long distances. However, despite the characterization of the genome of modern horses (3), an understanding of the genetic processes underlying horse domestication is still lacking. In other organisms, such an understanding is usually achieved by comparing the genomes of domesticated species and their wild relatives (4-6), but this approach is not directly applicable to horses. Recent genome-wide analyses have shown that Przewalski's horse, the last truly wild horse population remaining today, is not the direct ancestor of domesticated SignificanceThe domestication of the horse revolutionized warfare, trade, and the exchange of people and ideas. This at least 5,500-ylong process, which ultimately transformed wild horses into the hundreds of breeds living today, is difficult to reconstruct from archeological data...