The transitions from foraging to farming and later to pastoralism in Stone Age Eurasia (c. 11-3 thousand years before present, BP) represent some of the most dramatic lifestyle changes in human evolution. We sequenced 317 genomes of primarily Mesolithic and Neolithic individuals from across Eurasia combined with radiocarbon dates, stable isotope data, and pollen records. Genome imputation and co-analysis with previously published shotgun sequencing data resulted in >1600 complete ancient genome sequences offering fine-grained resolution into the Stone Age populations. We observe that: 1) Hunter-gatherer groups were more genetically diverse than previously known, and deeply divergent between western and eastern Eurasia. 2) We identify hitherto genetically undescribed hunter-gatherers from the Middle Don region that contributed ancestry to the later Yamnaya steppe pastoralists; 3) The genetic impact of the Neolithic transition was highly distinct, east and west of a boundary zone extending from the Black Sea to the Baltic. Large-scale shifts in genetic ancestry occurred to the west of this "Great Divide", including an almost complete replacement of hunter-gatherers in Denmark, while no substantial ancestry shifts took place during the same period to the east. This difference is also reflected in genetic relatedness within the populations, decreasing substantially in the west but not in the east where it remained high until c. 4,000 BP; 4) The second major genetic transformation around 5,000 BP happened at a much faster pace with Steppe-related ancestry reaching most parts of Europe within 1,000-years. Local Neolithic farmers admixed with incoming pastoralists in eastern, western, and southern Europe whereas Scandinavia experienced another near-complete population replacement. Similar dramatic turnover-patterns are evident in western Siberia; 5) Extensive regional differences in the ancestry components involved in these early events remain visible to this day, even within countries. Neolithic farmer ancestry is highest in southern and eastern England while Steppe-related ancestry is highest in the Celtic populations of Scotland, Wales, and Cornwall (this research has been conducted using the UK Biobank resource); 6) Shifts in diet, lifestyle and environment introduced new selection pressures involving at least 21 genomic regions. Most such variants were not universally selected across populations but were only advantageous in particular ancestral backgrounds. Contrary to previous claims, we find that selection on the FADS regions, associated with fatty acid metabolism, began before the Neolithisation of Europe. Similarly, the lactase persistence allele started increasing in frequency before the expansion of Steppe-related groups into Europe and has continued to increase up to the present. Along the genetic cline separating Mesolithic hunter-gatherers from Neolithic farmers, we find significant correlations with trait associations related to skin disorders, diet and lifestyle and mental health status, suggesting marked phenotypic differences between these groups with very different lifestyles. This work provides new insights into major transformations in recent human evolution, elucidating the complex interplay between selection and admixture that shaped patterns of genetic variation in modern populations.

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Background Extrachromosomal circular deoxyribonucleic acid (eccDNA) is evolving as a valuable biomarker, while little is known about its presence in urine. Methods Here, we report the discovery and analysis of urinary cell‐free eccDNAs (ucf‐eccDNAs) in healthy controls and patients with advanced chronic kidney disease (CKD) by Circle‐Seq. Results Millions of unique ucf‐eccDNAs were identified and comprehensively characterised. The ucf‐eccDNAs are GC‐rich. Most ucf‐eccDNAs are less than 1000 bp and are enriched in four pronounced peaks at 207, 358, 553 and 732 bp. Analysis of the genomic distribution of ucf‐eccDNAs shows that eccDNAs are found on all chromosomes but enriched on chromosomes 17, 19 and 20 with a high density of protein‐coding genes, CpG islands, short interspersed transposable elements (SINEs) and simple repeat elements. Analysis of eccDNA junction sequences further suggests that microhomology and palindromic repeats might be involved in eccDNA formation. The ucf‐eccDNAs in CKD patients are significantly higher than those in healthy controls. Moreover, eccDNA with miRNA genes is highly enriched in CKD ucf‐eccDNA. Conclusions This work discovers and provides the first deep characterisation of ucf‐eccDNAs and suggests ucf‐eccDNA as a valuable noninnvasive biomarker for urogenital disorder diagnosis and monitoring.

Abstract Circular DNA can arise from all parts of eukaryotic chromosomes. In yeast, circular ribosomal DNA (rDNA) accumulates dramatically as cells age, however little is known about the accumulation of other chromosome-derived circles or the contribution of such circles to genetic variation in aged cells. We profiled circular DNA in Saccharomyces cerevisiae populations sampled when young and after extensive aging. Young cells possessed highly diverse circular DNA populations but 94% of the circular DNA were lost after ∼15 divisions, whereas rDNA circles underwent massive accumulation to >95% of circular DNA. Circles present in both young and old cells were characterized by replication origins including circles from unique regions of the genome and repetitive regions: rDNA and telomeric Y’ regions. We further observed that circles can have flexible inheritance patterns: [HXT6/7circle] normally segregates to mother cells but in low glucose is present in up to 50% of cells, the majority of which must have inherited this circle from their mother. Interestingly, [HXT6/7circle] cells are eventually replaced by cells carrying stable chromosomal HXT6 HXT6/7 HXT7 amplifications, suggesting circular DNAs are intermediates in chromosomal amplifications. In conclusion, the heterogeneity of circular DNA offers flexibility in adaptation, but this heterogeneity is remarkably diminished with age.

Summary The Eurasian Holocene (beginning c. 12 thousand 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 an imputed dataset of >1600 complete ancient genome sequences, and new computational methods for locating selection in time and space, we reconstructed the selection landscape of the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify major selection signals related to metabolism, possibly associated with the dietary shift occurring in this period. We show that the selection on loci such as the FADS cluster, associated with fatty acid metabolism, and the lactase persistence locus, began earlier than previously thought. A substantial amount of selection is also found in the HLA region and other loci associated with immunity, possibly due to the increased exposure to pathogens during the Neolithic, which may explain the current high prevalence of auto-immune disease, such as psoriasis, due to genetic trade-offs. By using ancient populations to infer local ancestry tracks in hundreds of thousands of samples from the UK Biobank, we find strong genetic differentiation among ancient Europeans in loci associated with anthropometric traits and susceptibility to several diseases that contribute to present-day disease burden. These were previously thought to be caused by local selection, but in fact can be attributed to differential genetic contributions from various source populations that are ancestral to present-day Europeans. Thus, alleles associated with increased height seem to have increased in frequency following the Yamnaya migration into northwestern Europe around 5,000 years ago. Alleles associated with increased risk of some mood-related phenotypes are overrepresented in the farmer ancestry component entering Europe from Anatolia around 11,000 years ago, while western hunter-gatherers show a strikingly high contribution of alleles conferring risk of traits related to diabetes. Our results paint a picture of the combined contributions of migration and selection in shaping the phenotypic landscape of present-day Europeans that suggests a combination of ancient selection and migration, rather than recent local selection, is the primary driver of present-day phenotypic differences in Europe.

Circular DNA of chromosomal origin form from all parts of eukaryotic genomes. In yeast, circular rDNA accumulates as cells divide, contributing to replicative aging. However, little is known about how other chromosome-derived circles segregate and contribute to genetic variation as cells age. We identified circular DNA across the genome of young S. cerevisiae populations and their aged descendants. Young cells had highly diverse circular DNA populations, but lost 94% of the different circular DNA after 20 divisions. Circles present in both young and old cells were characterized by replication origins and included circles from unique regions of the genome, rDNA circles and telomeric Y' circles. The loss in genetic heterogeneity in aged cells was accompanied by massive accumulation of rDNA circles >95% of all circular DNA. We discovered circles had flexible inherence patterns.Glucose limited conditions selected for cells with glucose-transporter gene circles, [HXT6/7 circle ], and up to 50% of cells in a population carried them. [HXT6/7 circle ] cells were eventually substituted by cells carrying stable chromosomal HXT6 HXT6/7 HXT7 amplifications, suggesting circular DNA were intermediates in chromosomal amplifications. In conclusion, DNA circles can offer a flexible adaptive solution but cells lose genetic heterogeneity from circular DNA as they undergo replicative aging.Recent studies have shown that circular DNA form from all parts of eukaryotic genomes (20)(21)(22).While the majority of the circular DNA are smaller than 1 kilobase (kb) (20,22,23), some circular DNA are large enough to fully span transposons (24), centromeres, genes, and replication origins (13,20,22,(24)(25)(26)). Hence, circular DNA can acquire all the genetic elements required for the replication and propagation of the genetic material present on them. Yet, a global overview of how circular DNA segregates and affects aging is still missing. To obtain a global overview of how circular DNA segregates, we have applied the yeast Mother Enrichment Program (MEP) to obtain young and the corresponding aged cells (27) and combined it with our methods for purification and mapping of circular DNA (28, 29). This has allowed us to dissect the inheritance pattern of circular DNA while S. cerevisiae cells undergo replicative aging. To get a robust measure of the different circular DNA species present in young and aging cells, we have developed novel methods for mapping of circular DNA from both uniquely mappable and repetitive regions of the S. cerevisiae genome. Besides identifying circular DNA with different segregation patterns, we have adapted methods for quantifying the copy number levels of the detected circularDNA. This has allowed us to cluster circular DNA species and search for consensus elements that determine their inherence patterns. We find that most circular DNAs are lost from aging cells, while circular DNA with replication origins are prone to be maintained in cells as they age but only a few of these maintained circular DNA accumulate in a...

Summary With the rapid expansion of the capabilities of the DNA sequencers throughout the different sequencing generations, the quantity of generated data has likewise increased. This evolution has also led to new bioinformatical methods, for which in silico data has become crucial when verifying the accuracy of a model or the robustness of a genomic analysis pipeline. Here we present a multithreaded next-generation simulation tool for next-generation sequencing data (NGSNGS), which simulates reads faster than currently available methods and programs. NGSNGS can simulate reads with platform specific characteristics based on nucleotide quality score profiles, as well as including a post-mortem damage model which is relevant for simulating ancient DNA (aDNA). The simulated sequences are sampled (with replacement) from a reference DNA genome, which can represent a haploid genome, polyploid assemblies, or even population haplotypes and allows the user to simulate known variable sites directly. The program is implemented in a multithreading framework and is factors faster than currently available tools while extending their feature set and possible output formats. Availability The method and associated programs are released as open-source software, code and user manual are available at https://github.com/RAHenriksen/NGSNGS Supplementary information Supplementary data are available at Bioinformatics online.

Using ancient environmental DNA (eDNA) we reconstructed microbial and viral communities from the Kap København Formation in North Greenland. We find pioneer microbial communities, along with likely dormant methanogens from the permafrost's seed bank. Our findings reveal that at the time of the formation, the terrestrial input of the Kap København site originated from a palustrine wetland, suggesting non-permafrost conditions. During this time, detection of methanogenic archaea and carbon processing pathways suggests a moderate strengthening of methane emissions through the northward expansion of wetlands. Intriguingly, we discover a remarkable sequence similarity (>98%) between pioneer methanogens and present-day thawing permafrost counterparts. This suggests that not all microbes respond uniformly to environmental change over geological timescales, but that some microbial taxa's adaptability and resilience remain constant over time. Our findings further suggest that the composition of microbial communities is changing prior to plant communities as a result of global warming.