Global diversity, recurrent evolution, and recent selection on amylase structural haplotypes in humans.

The adoption of agriculture, first documented ~12,000 years ago in the Fertile Crescent, triggered a rapid shift toward starch-rich diets in human populations. Amylase genes facilitate starch digestion and increased salivary amylase copy number has been observed in some modern human populations with high starch intake, though evidence of recent selection is lacking. Here, using 52 long-read diploid assemblies and short read data from ~5,600 contemporary and ancient humans, we resolve the diversity, evolutionary history, and selective impact of structural variation at the amylase locus. We find that both salivary and pancreatic amylase genes have higher copy numbers in populations with agricultural subsistence compared to fishing, hunting, and pastoral groups. We identify 28 distinct amylase structural architectures and demonstrate that identical structures have arisen independently multiple times throughout recent human history. Using a pangenome graph-based approach to infer structural haplotypes across thousands of humans, we identify extensively duplicated haplotypes present at higher frequencies in modern agricultural populations. Leveraging 534 ancient human genomes we find that duplication-containing haplotypes have increased in frequency more than seven-fold over the last 12,000 years providing evidence for recent selection in Eurasians at this locus comparable in magnitude to that at lactase. Together, our study highlights the strong impact of the agricultural revolution on human genomes and the importance of long-read sequencing in identifying signatures of selection at structurally complex loci.

The selection landscape and genetic legacy of ancient Eurasians.

The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer's disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Multielectrode Cortical Stimulation Selectively Induces Unidirectional Wave Propagation of Excitatory Neuronal Activity in Biophysical Neural Model.

Cortical stimulation is emerging as an experimental tool in basic research and a promising therapy for a range of neuropsychiatric conditions. As multielectrode arrays enter clinical practice, the possibility of using spatiotemporal patterns of electrical stimulation to induce desired physiological patterns has become theoretically possible, but in practice can only be implemented by trial-and-error because of a lack of predictive models. Experimental evidence increasingly establishes traveling waves as fundamental to cortical information-processing, but we lack an understanding of how to control wave properties despite rapidly improving technologies. This study uses a hybrid biophysical-anatomical and neural-computational model to predict and understand how a simple pattern of cortical surface stimulation could induce directional traveling waves via asymmetric activation of inhibitory interneurons. We found that pyramidal cells and basket cells are highly activated by the anodal electrode and minimally activated by the cathodal electrodes, while Martinotti cells are moderately activated by both electrodes but exhibit a slight preference for cathodal stimulation. Network model simulations found that this asymmetrical activation results in a traveling wave in superficial excitatory cells that propagates unidirectionally away from the electrode array. Our study reveals how asymmetric electrical stimulation can easily facilitate traveling waves by relying on two distinct types of inhibitory interneuron activity to shape and sustain the spatiotemporal dynamics of endogenous local circuit mechanisms.SIGNIFICANCE STATEMENT Electrical brain stimulation is becoming increasingly useful to probe the workings of brain and to treat a variety of neuropsychiatric disorders. However, stimulation is currently performed in a trial-and-error fashion as there are no methods to predict how different electrode arrangements and stimulation paradigms will affect brain functioning. In this study, we demonstrate a hybrid modeling approach, which makes experimentally testable predictions that bridge the gap between the microscale effects of multielectrode stimulation and the resultant circuit dynamics at the mesoscale. Our results show how custom stimulation paradigms can induce predictable, persistent changes in brain activity, which has the potential to restore normal brain function and become a powerful therapy for neurological and psychiatric conditions.