Highlights d Ultra-deep rRNA-depleted RNA sequencing of 144 localized prostate tumors d Fusion gene profiles differentiate localized from metastatic disease d Widespread RNA circularization events define clinically distinct tumor subtypes d Functional screening reveals pervasive circular isoformspecific essentiality

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...

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Humans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that: (i) both new and low-frequency variants are significantly more deleterious in front than in core individuals, (ii) equally deleterious mutations are at higher frequencies in front individuals, and (iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past six to nine generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection mainly due to higher rates of genetic drift on the wave front. Demographic inference and modeling of the evolution of rare variants suggest lower effective size on the front, and lead to an estimation of selection coefficients that increase with conservation scores. Even though range expansions have had a relatively limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions of Quebec.