1The extent to which selection has shaped present-day human populations has attracted 2 intense scrutiny, and examples of local adaptations abound. However, the evolutionary 3 trajectory of alleles that, today, are deleterious has received much less attention. To 4 address this question, the genomes of 2,062 individuals, including 1,179 ancient humans, 5 were reanalyzed to assess how frequencies of risk alleles and their homozygosity changed 6 through space and time in Europe over the past 45,000 years. While the overall deleterious 7 homozygosity has consistently decreased, risk alleles have steadily increased in frequency 8 over that period of time. Those that increased most are associated with diseases such as 9 asthma, Crohn disease, diabetes and obesity, which are highly prevalent in present-day 10 populations. These findings may not run against the existence of local adaptations, but 11 highlight the limitations imposed by drift and population dynamics on the strength of 12 selection in purging deleterious mutations from human populations. 13 15 Depletion (CADD).16 3 Main Text 17The role played by natural selection in shaping present-day human populations has re-18 ceived extensive scrutiny [1, 2, 3], especially in the context of local adaptations [4]. ever, most studies to date assume, either explicitly or not, that populations have been in 20 their current locations long enough to adapt to local conditions [5], and that they were 21 large enough to allow for the action of selection [6]. If these conditions were satisfied, not 22 only should selection be effective at promoting local adaptations, but deleterious alleles 23 should also be eliminated over time. Surprisingly, this question has only been examined 24 by comparing present-day modern humans from Africa and Europe [7], leading to the 25 consensus that selection was as effective in Europeans as in Africans [8, 9] but without 26 really assessing the effectiveness of selection on a large data set [10]. Here, I examine 27 this question directly, based on the genotype of not only present-day humans, but also of 28 > 1, 000 ancient humans over the past 45,000 years.
29In order to trace the evolutionary trajectory of deleterious alleles in human populations 30 over time, the genotypes of 2,062 individuals, of which 1,179 were ancient humans, were 31 assessed at about 1.2 million Single Nucleotide Polymorphisms (SNPs; the '1240k capture'
32[11]). The present study focuses on individuals sampled throughout Europe, from the 33 Atlantic to the Ural Mountains, as this is where most ancient DNA has been recovered 34 and genotyped throughout the world. To take into account the history of admixture 35 and replacement events characterizing Europe [12, 11], this region was split into four 36 quadrants along two orthogonal axes roughly cutting through the Alps (Figure 1). These 37 four quadrants represent approximately four distinct areas that played significant roles in 38 the three peopling waves that affected Europe, first from the Fertile Crescent (Q4 in Fi...