Cultivating Farmers: Were the ancestors of modern Europeans the local hunter-gatherers who assimilated farming practices from neighboring cultures, or were they farmers who migrated from the Near East in the early Neolithic? By analyzing ancient hunter-gatherer skeletal DNA from 2300 to 13,400 B.C.E. Bramanti et al. (p. 137 , published online 3 September) investigated the genetic relationship of European Ice Age hunter-gatherers, the first farmers of Europe, and modern Europeans. The results reject the hypothesis of direct continuity between hunter-gatherers and early farmers and between hunter-gatherers and modern Europeans. Major parts of central and northern Europe were colonized by incoming farmers 7500 years ago, who were not descended from the resident hunter-gatherers. Thus, migration rather than cultural diffusion was the driver of farming communities in Europe.

The ancestry of modern Europeans is a subject of debate among geneticists, archaeologists, and anthropologists. A crucial question is the extent to which Europeans are descended from the first European farmers in the Neolithic Age 7500 years ago or from Paleolithic hunter-gatherers who were present in Europe since 40,000 years ago. Here we present an analysis of ancient DNA from early European farmers. We successfully extracted and sequenced intact stretches of maternally inherited mitochondrial DNA (mtDNA) from 24 out of 57 Neolithic skeletons from various locations in Germany, Austria, and Hungary. We found that 25% of the Neolithic farmers had one characteristic mtDNA type and that this type formerly was widespread among Neolithic farmers in Central Europe. Europeans today have a 150-times lower frequency (0.2%) of this mtDNA type, revealing that these first Neolithic farmers did not have a strong genetic influence on modern European female lineages. Our finding lends weight to a proposed Paleolithic ancestry for modern Europeans.

Lactase persistence (LP), the dominant Mendelian trait conferring the ability to digest the milk sugar lactose in adults, has risen to high frequency in central and northern Europeans in the last 20,000 years. This trait is likely to have conferred a selective advantage in individuals who consume appreciable amounts of unfermented milk. Some have argued for the “culture-historical hypothesis,” whereby LP alleles were rare until the advent of dairying early in the Neolithic but then rose rapidly in frequency under natural selection. Others favor the “reverse cause hypothesis,” whereby dairying was adopted in populations with preadaptive high LP allele frequencies. Analysis based on the conservation of lactase gene haplotypes indicates a recent origin and high selection coefficients for LP, although it has not been possible to say whether early Neolithic European populations were lactase persistent at appreciable frequencies. We developed a stepwise strategy for obtaining reliable nuclear ancient DNA from ancient skeletons, based on ( i ) the selection of skeletons from archaeological sites that showed excellent biomolecular preservation, ( ii ) obtaining highly reproducible human mitochondrial DNA sequences, and ( iii ) reliable short tandem repeat (STR) genotypes from the same specimens. By applying this experimental strategy, we have obtained high-confidence LP-associated genotypes from eight Neolithic and one Mesolithic human remains, using a range of strict criteria for ancient DNA work. We did not observe the allele most commonly associated with LP in Europeans, thus providing evidence for the culture-historical hypothesis, and indicating that LP was rare in early European farmers.

In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex- or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection.

From AD 1347 to AD 1353, the Black Death killed tens of millions of people in Europe, leaving misery and devastation in its wake, with successive epidemics ravaging the continent until the 18^th century. The etiology of this disease has remained highly controversial, ranging from claims based on genetics and the historical descriptions of symptoms that it was caused by Yersinia pestis to conclusions that it must have been caused by other pathogens. It has also been disputed whether plague had the same etiology in northern and southern Europe. Here we identified DNA and protein signatures specific for Y. pestis in human skeletons from mass graves in northern, central and southern Europe that were associated archaeologically with the Black Death and subsequent resurgences. We confirm that Y. pestis caused the Black Death and later epidemics on the entire European continent over the course of four centuries. Furthermore, on the basis of 17 single nucleotide polymorphisms plus the absence of a deletion in glpD gene, our aDNA results identified two previously unknown but related clades of Y. pestis associated with distinct medieval mass graves. These findings suggest that plague was imported to Europe on two or more occasions, each following a distinct route. These two clades are ancestral to modern isolates of Y. pestis biovars Orientalis and Medievalis. Our results clarify the etiology of the Black Death and provide a paradigm for a detailed historical reconstruction of the infection routes followed by this disease. Several historical epidemic waves of plague have been attributed to Yersinia pestis, the etiologic agent of modern plague. The most famous of these was the second pandemic which was active in Europe from AD 1347 until 1750, and began with the ‘Black Death’. The most informative method to establish the etiological nature of these ancient infections should be the analysis of ancient DNA, but the results of this method have been controversial. Here, by combining ancient DNA analyses and protein-specific detection, we demonstrate unambiguously that Y. pestis caused the Black Death. Furthermore, we show that at least two variants of Y. pestis spread over Europe during the second pandemic. The analysis of up to 20 diagnostic markers reveals that the two variants evolved near the time that phylogenetic branches 1 and 2 separated and may no longer exist. Our results thus resolve a long-standing debate about the etiology of the Black Death and provide key information about the evolution of the plague bacillus and the spread of the disease during the Middle Ages.

Significance: The second plague pandemic in medieval Europe started with the Black Death epidemic of 1347–1353 and killed millions of people over a time span of four centuries. It is commonly thought that after its initial introduction from Asia, the disease persisted in Europe in rodent reservoirs until it eventually disappeared. Here, we show that climate-driven outbreaks ofYersinia pestisin Asian rodent plague reservoirs are significantly associated with new waves of plague arriving into Europe through its maritime trade network with Asia. This association strongly suggests that the bacterium was continuously reimported into Europe during the second plague pandemic, and offers an alternative explanation to putative European rodent reservoirs for how the disease could have persisted in Europe for so long.