The aim of the Path2Bos project is to reconstruct the evolutionary path of cattle from its domestication starting about 10,000 years ago in Anatolia, during its later spread into Europe and Africa and up to now, through a paleogenomic analysis of fossils, the direct witnesses of evolution. The goal is to identify genomic regions that were selected at the early stages of domestication, corresponding to basic phenotypes that should be preserved in ongoing genetic selection schemes. The project is based on a previous paleogenetic characterization of a large number (~ 700) of 9,000- to 1,000-year-old archaeological bones of ancient domesticated cattle and their wild ancestors, the aurochs. We have genotyped the mitochondrial genomes and sequenced the hypervariable regions of almost 200 of these ancient bones, allowing us to assign reliably their mitochondrial haplogroups and to follow the evolution of populations from their initial domestication in Anatolia during the Neolithic as well as their spread and evolution in Europe and North Africa until the Middle Ages. Using sequence capture, we obtained complete mitogenomes from 40 of these samples representing the various clades, reconstructed the evolution and timing of radiation of aurochs’ populations, and untangled the impacts on population diversity of both climate changes during the Pleistocene-Holocene transition and initial domestication. We have sequenced the genome of a 9,000-year-old aurochs from the domestication centre in Anatolia that will serve as a reference genome to follow the genomic changes and selective sweeps during the domestication process. We propose to sequence about 30 of these ancient genomes and to compare them with genomes and phenotypic records from modern domestic animals to reconstruct many aspects of the selection pressure exerted during different prehistoric and historic periods. We will also sequence several individuals from modern hardy breeds to generate reference genetic data from breeds that have escaped recent selection schemes or that were selected for alternative phenotypes. Our data will be used in combination with modern genomic data from the 1,000 Bull Genomes consortium in various complementary ways to identify and to date signatures of selection during the cattle domestication process. We will screen for selection events that are either recent or old, complete or ongoing, acting on new variants or on standing variation. Using powerful tools to detect selective sweeps in genomes, ancient genomic data will provide the ability to date the various selection events, to identify the population(s) of origins onto which selection was exerted and to explore the validity of the various demographic models used to detect selective sweeps from modern genomic data. We will also use extensive GWAS data, produced by one of us using modern cattle, to reconstruct the past evolution of complex multigenic traits. Path2Bos will (1) improve the power and accuracy of the identification of genomic regions under selection, (2) estimate the strength of selection and date the origin of the corresponding selective events, (3) identify variants that were selected in the past and that have been lost in modern selection schemes, thereby pinpointing the genetic bases of phenotypic traits that might be useful to preserve for the long-term sustainability of cattle husbandry. Thus, it will provide an original and very useful cattle genome annotation data source to complement the genomic characterization efforts of modern cattle breeds and enrich the current selection strategies. A strong point of Path2Bos is the complementarity of the expertise and resources, including preliminary data, of the consortium partners, in particular paleogenomics and a large collection of characterized archeological samples, involvement in the 1000 Bull Genomes consortium and GWAS, selective sweep method developments and analyses of genomes and a high-throughput sequencing facility.