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Post by Admin on Jan 16, 2020 2:24:11 GMT
For some 200,000 years, Homo sapiens and Neanderthals coexisted on Earth. But then, around 40,000 years ago, Neanderthals disappear from the fossil record, never to be seen again. That’s when most archaeologists think our evolutionary cousins went extinct, based on exhaustive reviews of radiocarbon dates associated with Neanderthal fossils and artifacts. There’s no uncontested evidence for the species persisting past that time.  One team of researchers says they’ve found such a case: the site of Byzovaya, in Russia’s Ural Mountains. According to their 2011 study, Neanderthals survived there until about 31,000 years ago — 9,000 years after the presumed extinction date. Not only would these hardy few constitute the longest-lasting Neanderthals, they’d also be the farthest north — nearly 700 miles beyond the species’ known northern limit. Seclusion could have shielded the group from extinction, at least for a few more millennia, and delayed their discovery by modern-day archaeologists. But other researchers reject this notion and maintain that modern humans, not Neanderthals, inhabited the site. Today, nearly a decade after the debate unfolded in Science, the matter remains unsettled.  Proving Neanderthal Persistence More than 1,000 miles from Moscow, Byzovaya sits on a river bluff in the foothills of the Ural Mountains, which form the border between Europe and Asia. At 65 degrees latitude, the site is about 100 miles shy of the Arctic Circle. Beginning in the 1960s, Byzovaya has been excavated several times by different research groups. Over the years, archaeologists have unearthed more than 300 stone artifacts and 4,000 animal bones, mostly from woolly mammoth. Handcrafted tools and butchered bones prove some kind of humans (a group that includes Neanderthals) were once there, but leave unanswered the mystery of who these people were. The latest investigation, by a French-Russian team, produced 33 radiocarbon dates from animal bones found with the artifacts. The new data suggest the finds are 31,400 to 34,600 years old. On its own, that result is exciting, but also agrees with expectations: Other archaeological sites 30,000 to 43,000 years old dot the Urals. And a few sites this age or slightly older have been found even farther north, within the Arctic Circle. Most researchers assume H. sapiens alone occupied these locales — that only our species had the smarts and technology (like tailored clothing and boots) necessary to survive at such high latitudes. But the Byzovaya study caused a stir because of its other, more provocative conclusion. The artifacts were made by Neanderthals — the last and northernmost of their kind. Telltale Tools The trouble with the claim: No Neanderthal — or any human — fossils have been found at Byzovaya. Just stone tools and animal bones. To definitively prove a Neanderthal presence, researchers would need bones bearing Neanderthal DNA. Lacking this, the conclusion comes from analysis of the 313 stone artifacts recovered from Byzovaya. Based on comparisons with well-accepted Neanderthal sites in central and eastern Europe, the scientists contend the tool types and style of craftsmanship are distinctly Neanderthal. Contemporaneous H. sapiens in Eurasia didn’t make stuff like that, they argue. The reasoning may sound flimsy, but archaeologists routinely use artifact style to infer the presence of ancient human species or cultures. Human fossils are really rare. Most sites only have artifacts. For better or worse, artifacts often provide our best guess of who was there at fossil-free sites. (Trust me, I wrote a dissertation on the matter.) Which brings us back to the stalemate over Byzovaya. Different researchers, viewing the same material, came to differing conclusions. Another group of stone-tool experts thinks the finds more closely resemble artifacts from similarly aged sites in western Russia that have H. sapiens skeletons. In this view, Byzovaya was just another modern human spot.  DNA Update To date, there are still no DNA-bearing human fossils from Byzovaya. But ancient genomes have been recovered from other sites, which figure into the debate. There’s now DNA data confirming, beyond doubt, the H. sapiens status of skeletons from two western Russian sites (Kostenki and Sungir) with artifacts similar to those from Byzovaya. This strengthens the case that H. sapiens occupied Byzovaya. Except that the sites are not that close: From Byzovaya, it’s more than 700 and 1,000 miles to Sungir and Kostenki, respectively. They’re just the sites nearest in both time and space, with fossils as well as similar-looking artifacts. We still don’t know which humans left artifacts and butchered animals at Byzovaya. They may have been Earth’s last Neanderthals or modern humans venturing polar-ward. Alternatively, the group could have comprised a mix of Neanderthals and H. sapiens, or even another type of human, like Denisovans. Given the vastness of the Eurasian landmass, it’s highly possible some groups of Neanderthals persisted in remote pockets — missing the memo their species was destined for extinction. |
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Post by Admin on Jun 11, 2020 23:14:07 GMT
More than 120,000 novel human genetic variations that affect large regions of DNA have been discovered, some of which are linked to immune response, disease susceptibility or digestion. Scientists at the Wellcome Sanger Institute identified these changes affecting multiple bases of DNA, known as structural variations, in a study of the most diverse worldwide populations examined to date. This included variations in medically-important genes in populations from Papua New Guinea that were inherited from Denisovan ancestors. The resource, published today in Cell, adds new regions of sequence to the human reference genome, the world standard for all of human genetics, which is nevertheless incomplete. These previously-unknown variations in medically-important genes, which could affect the efficacy of medical treatments in certain populations, will be a valuable resource for the field of precision medicine around the globe.  Structural variations are genetic changes that can encompass anything from a few to millions of base pairs of DNA and are therefore particularly likely to affect how genes function. Some genes, such as those that influence immune response, are considered to be 'medically important'. DNA changes affecting how these genes function can lead to health problems or increased resistance or susceptibility to particular diseases. Up until now, most large-scale genetic studies have generally focused on changes affecting single base pairs of DNA. Scientists at the Wellcome Sanger Institute had previously led the sequencing of 911 genomes from 54 geographically, linguistically and culturally diverse populations from across the globe, and have now searched for structural variations in these sequences. The sequences were compared to the human reference genome to create a catalogue of structural variations, over three quarters of which were previously unknown. The team then investigated how common these structural variations are in each of the 54 populations, and which of them were inherited from Neanderthal or Denisovan ancestors. Among the 126,018 structural variations discovered were medically-important variations inherited from Denisovan ancestors in Oceanian populations from Papua New Guinea and nearby, including a high-frequency deletion in the AQR gene that plays a role in detection of viruses and regulation of antiviral immune response. Mohamed Almarri, first author of the study and Ph.D. student at the Wellcome Sanger Institute, said: "By analysing the genomes of understudied populations we've been able to find high-frequency structural variations not uncovered by previous large-scale sequencing projects. Several of these are in medically-important genes that tell us how a population has evolved to resist a certain disease or why they might be susceptible to others. This is vital knowledge and will help to ensure that treatments can be tailored to each specific population." Other notable structural variations were uncovered by the study that, together with existing knowledge of human evolution and the role of specific genes, shine a light on how individual populations have evolved. The Karitiana people, who reside in modern-day Brazil, were found to carry a variation in the MGAM gene that affects starch digestion. The Karitiana diet is derived from fishing, hunting and farming, so a decrease in starch digestion is probably disadvantageous and therefore surprising. It is thought that bad luck may have concentrated this variation in the small population that survived a population crash within the last 5,000 years. The team also discovered novel 'runaway duplications', where populations have evolved to carry multiple copies of genes. For example, all of the African populations included in the study carried multiple copies of the HPR gene, which is associated with resistance to sleeping sickness. The highest numbers of copies (up to nine) were carried by Central and West African populations, where the disease is most prevalent. Dr. Ed Hollox, an expert in the field from the University of Leicester, said: "This is a very valuable study showing the importance of structural variation of the human genome in the genetic diversity of humans around the world. The work supports the concept that some human adaptations to different environments are due to the loss or gain of whole genes, or parts of genes. Structural variation can be challenging to find, and this study also provides a well-founded structural variation reference set which will serve as an important springboard for future studies." The study adds almost two million newly-identified base pairs to the human reference genome sequence. Because the human reference genome was assembled from a small number of people, regions of DNA that were not present in these individuals are missing from the reference sequence.  The team recreated 25 diverse human genomes from scratch using a recent technological innovation called de novo genome assembly. By directly comparing these assembled genomes to the reference, the researchers were able to identify missing sequences present in multiple populations. This illustrates the limitation of a single human reference and the need for high-quality reference genomes from diverse populations. Dr. Yali Xue, recently retired from the Wellcome Sanger Institute, said: "Structural variants are complicated yet very important functionally, evolutionarily and medically. The discovery of these new structural variations provides one of the richest resources of this kind of variation so far, which not only offers unique insights into population histories and improves the currently used human reference genome, but will also substantially benefit future medical studies." Explore further Global human genomes reveal rich genetic diversity shaped by complex evolutionary history More information: Mohamed A. Almarri, Anders Bergström and Javier Prado-Martinez et al. (2020). Population Structure, Stratification and Introgression of Human Structural Variation. Cell. DOI: doi.org/10.1016/j.cell.2020.05.024 |
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Post by Admin on Jun 12, 2020 6:13:44 GMT
Population Structure, Stratification and Introgression of Human Structural Variation Mohamed A. Almarri, Anders Bergström, Javier Prado-Martinez, Fengtang Yang, Beiyuan Fu, Alistair S. Dunham, Yuan Chen, Matthew E. Hurles, Chris Tyler-Smith, Yali Xue doi: doi.org/10.1101/746172Abstract Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, yet are still understudied. Here, we present a comprehensive analysis of deletions, duplications, insertions, inversions and non-reference unique insertions in the Human Genome Diversity Project (HGDP-CEPH) panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify in total 126,018 structural variants (25,588 <100 bp in size), of which 78% are novel. Some reach high frequency and are private to continental groups or even individual populations, including a deletion in the maltase-glucoamylase gene MGAM involved in starch digestion, in the South American Karitiana and a deletion in the Central African Mbuti in SIGLEC5, potentially leading to immune hyperactivity. We discover a dynamic range of copy number expansions and find cases of regionally-restricted runaway duplications, for example, 18 copies near the olfactory receptor OR7D2 in East Asia and in the clinically-relevant HCAR2 in Central Asia. We identify highly-stratified putatively introgressed variants from Neanderthals or Denisovans, some of which, like a deletion within AQR in Papuans, are almost fixed in individual populations. Finally, by de novo assembly of 25 genomes using linked-read sequencing we discover 1631 breakpoint-resolved unique insertions, in aggregate accounting for 1.9 Mb of sequence absent from the GRCh38 reference. These insertions show population structure and some reside in functional regions, illustrating the limitation of a single human reference and the need for high-quality genomes from diverse populations to fully discover and understand human genetic variation.  Figure 1: The HGDP dataset and population structure. A: The HGDP dataset, each point and colour represents a population and its regional label, respectively. Colours of regional groups are consistent throughout the study. See Table S1 for more details. B: UMAP of biallelic deletions genotypes. See Figure S6 for more details. C: UMAP of insertions. D: UMAP of biallelic duplications. E: UMAP of multiallelic variants. Introduction Despite the progress in sampling many populations, human genomics research is still not fully reflective of the diversity found globally (Sirugo et al., 2019). Understudied populations limit our knowledge of genetic variation and population history, and their inclusion is needed to ensure they benefit from future developments in genomic medicine. Whole-genome sequencing projects have provided unprecedented insights into the evolutionary history of our species; however, they have mostly concentrated on substitutions at individual sites, although structural variants (affecting > 50bp), which include deletions, duplications, inversions and insertions, contribute a greater diversity at the nucleotide level than any other class of variation and are important in genome evolution and disease susceptibility (Huddleston & Eichler 2016). Previous studies surveying global population structural variation have examined metropolitan populations at low-coverage (Sudmant et al., 2015a), or a few samples from a larger number of populations (Sudmant et al., 2015b), allowing broad continental comparisons but limiting detailed analysis within each continental group and population. In this study, we present the structural variation analysis of the Human Genome Diversity Project (HGDP)-CEPH panel (Figure 1A), a dataset composed of 911 samples from 54 populations of linguistic, anthropological and evolutionary interest (Cann et al., 2002). We generate a comprehensive resource of structural variants from these diverse and understudied populations, explore the structure of different classes of structural variation, characterize regional and population-specific variants and expansions, discover putatively introgressed variants and identify sequences missing from the GRCh38 reference. |
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Post by Admin on Jun 12, 2020 20:13:18 GMT
Results Variant Discovery and Comparison with Published Datasets We generated 911 whole-genome sequences at an average depth of 36x and mapped reads to the GRCh38 reference (Bergström et al., 2019). As the dataset was generated from lymphoblastoid cell lines, we searched for potential cell-line artefacts by analysing coverage across the genome and excluded samples containing multiple aneuploidies, while masking regions which show more limited aberrations (Figure S1). We find many more gains of chromosomes than losses, and in agreement with a previous cell-line based study (Redon et al. 2006), we observe that most trisomies seem to affect chromosomes 9 and 12, suggesting that they contain sequences that enhance proliferation once duplicated in culture. Nevertheless, these cell line artefacts can readily be recognised, and are excluded from the results below.  Figure S1: Coverage plots illustrating examples of samples that were excluded from the analysis because of likely cell-line artefacts. Coverage was calculated at ∼300,000 single positions across the genome and a rolling mean was plotted normalized by the genome-wide median. Left: HGDP01283 (chr1-10) which shows artefacts across multiple chromosomes. Right: HGDP00452 (chr11-21) which shows a large duplication in most of chromosome 11 in addition to smaller duplications in other chromosomes. Orange bars indicate coverage is >25% than chromosome average, green <25%. Blue represents centromeres. We identified 126,018 structural variants relative to the reference. These included 25,588 (∼20% of the total) that are smaller than 100bp. We compared our dataset to published structural variation catalogues (Sudmant, et al. 2015a; Sudmant, et al. 2015b), and find that ∼78% of the variants identified in our dataset are not present in the previous studies. Despite having a smaller sample size compared to the 1000 Genomes phase 3 release (Sudmant, et al. 2015a), we discover a higher total number of variants across all different classes of variants investigated. These novel calls are not limited to rare variants, as a considerable number of common and even high-frequency variants are found in regional groups and individual populations (Figure S9). The increased sensitivity reflects the higher coverage, longer reads, improved discovery tools and the large number of diverse populations in our study. Notably, our resource identifies the abundant, but understudied class of small variants (50bp – 100bp), which were not particularly characterized by the Simons Genome Diversity Project (Sudmant, et al. 2015b). At this size range, ∼91% of variants in our dataset are not present in either published catalogues. Collectively, this illustrates that a substantial amount of global structural variation was previously undocumented, emphasizing the importance of studying underrepresented human populations.  Figure S2: Size distribution of identified variants that passed all filters and were included in the final callset. Note the differences in scales between the two plots. Top: Manta+Graphtyper. Bottom: GenomeSTRiP – green line shows variants that have both deletion and duplication alleles. Population Structure A uniform manifold approximation and projection (UMAP) of deletion genotypes shows clear separation of continental groups, and in many cases even individual populations are distinguished (Figure 1B). Deeply divergent African populations such as the Mbuti, Biaka and San form their own clusters away from the rest of the African populations; admixed groups such as the Hazara and Uygur cluster separately from the Central & South Asian and East Asian groups, while drifted populations such as the Kalash in addition to American and Oceanian populations are clearly differentiated. For less clearly defined populations projecting into continental clusters, we observe examples of finer structure with samples from individual populations appearing closer to themselves relative to other groups (Figure S6). Insertions, duplications, multiallelic variants and inversions also show some degree of population structure, although less defined in comparison to deletions (Figures 1C-E and S4). Strikingly, the Oceanian populations always remain well-differentiated. Consequently, we find that all classes of genetic variation show population structure, with the observed differences likely reflecting the varying mutational patterns generating each class of structural variant, in addition to the overall number of discovered variants in each class. |
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Post by Admin on Jun 13, 2020 6:46:18 GMT
 Figure S3: Quality checks on genotyping. Top: Correlation of allele frequency of variants identified by both Manta+Graphtyper and GenomeSTRiP (African-specific variants). Bottom: Allele frequency correlations between variants identified in the 1000G and the HGDP Manta+Graphtyper callset (common African-specific variants).  Figure S4A: PCA (1-10) of GenomeSTRiP biallelic deletion genotypes by sample library preparation and sequencing location. Population Stratification and Selection Selective pressures can result in highly stratified variants between populations. We assessed the relationship between average population differentiation and the maximal variant allele frequency difference for each population pair (Figure 2A-C). Outliers in this relationship, i.e. variants that show a higher allele frequency difference than expected, have been proposed to be under selection (Coop et al., 2009; Huerta-Sanchez et al., 2014). Both deletions and insertions show similar distributions, while biallelic duplications display lower stratification. We do see some notable outliers, for example the Lowland/Sepik Papuans are almost fixed (86%) for a deletion in HBA2, which is absent in Papuan Highlanders. High frequencies of α-globin deletions have been suggested to be protective against malaria, which is not found in the highlands of Papua New Guinea, but is present in the lowlands (Yenchitsomanus et al., 1985, Flint et al., 1986). On the other hand, Papuan Highlanders have a small insertion (123bp) near an exon of VGLL4 at 93% frequency which is markedly less common in Papuan Lowlands (7%). We also find a deletion within MYO5B that is particularly common (88%) in the Lahu from China, a population shown to have high numbers of private single nucleotide variants in addition to carrying rare Y-chromosome lineages (Bergström et al., 2019).  Figure 2: Population stratification of structural variants. A: Maximum allele frequency difference of deletions as a function of population differentiation for 1431 pairwise population comparisons. Blue curve represents loess fits. B-C: Same as A but for insertion and biallelic duplications, respectively. D: High frequency Oceanian-specific variants (>30% frequency). Each point represents a variant with the x-axis illustrating its frequency. Random noise is added to aid visualization. Almost all variants are shared with the Denisovan genome and are within (bold) or near the illustrated genes. E: Fluorescent in situ hybridization illustrating the 16p12 Oceanian-specific duplication shared with Denisova in a homozygous state (cell-line GM10543). Yellow arrows show reference and red arrow illustrate duplication. See Figure S12-13 for more details. F: Distinct deletions at the SIGLEC5/SIGLEC14 locus in an Mbuti sample (HGDP00450) resolved using linked-reads. One haplotype (top) carries the Mbuti-specific variant that deletes most exons in SIGLEC5 and is present at high frequency (54%), while the second haplotype (bottom) carries a globally common deletion that deletes SIGLEC14, creating a fused gene (See supplementary information for more details). The large number of samples per population allowed us to investigate population-private variants (Figure S7). We searched for functional effects of such variants and found a 14kb deletion in the South American Karitiana population at 40% frequency. This variant removes the 5’ upstream region of MGAM up to the first exon, potentially inactivating the gene which encodes Maltase-glucoamylase, an enzyme highly expressed in the small intestine and involved in the digestion of dietary starches (Nichols et al., 2003). Interestingly, a recent ancient DNA study of South Americans has suggested that selection acted on this gene in ancient Andean individuals, possibly as a result of their transition to agriculture (Lindo et al., 2018). This gene has also been proposed to be under selection in dogs, due to adaptation to a starch-rich diet during domestication (Axelsson et al., 2013). However, the high frequency and presence of individuals homozygous for this deletion suggests that purifying selection on the ability to digest starch has been relaxed in the history of the Karitiana. |
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