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Post by Admin on Feb 8, 2018 18:42:04 GMT
Mapping the blue-eyed boy's genes is part of ongoing effort to uncover the DNA of ancient humans. The new study in the journal Nature, led by Inigo Olalde of Spain's Institut de Biología Evolutiva in Barcelona, reports the genetic map of a skeleton found in a Spanish cave. The researchers extracted DNA from a tooth found with the skeleton of man, dubbed La Brana 1, uncovered in a cave near León, Spain, in 2006. In the lab, they compared the DNA from the man with DNA from other Stone Age Europeans, such as Ötzi, the 5,300-year-old "Iceman" of the Alps (whose people were farmers), and older, partial samples of genes recovered from hunter-gatherer burials in Sweden, Finland, and Siberia. Around 7,000 years ago, a Stone Age culture spread across Europe, made famous by discoveries of small, rotund "Venus" figurines found in their burials. The study results suggest those people were genetically connected—one thin population of dark-haired hunter-gatherers whose domain reached from Spain to Siberia. They were also partly the ancestors of many of today's northern Europeans. Moreover, the ancient Spaniard had multiple genes linked to disease immunity, resistance to bacteria, and risks for musculoskeletal ailments, ones seen in people today. Understanding the origin of these genes can help better explain their function, which could aid medical studies, for example. For fans of the "Paleo Diet" and other get-back-to-nature notions, the study brings some good news, suggesting that people carry around plenty of genes left over from their primeval forebears. The survival of some disease-resistance genes that mattered greatly in antiquity, as shown by their continuity in modern humans, also can help show how evolution worked its magic on us, and is still working today.
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Post by Admin on Feb 9, 2018 18:50:01 GMT
“Cheddar Man” – the oldest skeleton found in the UK – had black skin, curly hair and blue eyes. And now experts say analysing the 10,000-year-old remains has changed the idea of what it means to be British. Prof Ian Barnes and Dr Selina Brace, of London’s Natural History Museum, extracted hair and skin DNA profiles from the bones which were found at Gough’s Cave in Cheddar Gorge, Som, in 1903. Model makers Adrie and Alfons Kennis then reconstructed his head using a 3D printer and a scanner made for the International Space Station. Cheddar Man was likely to be a close genetic relative of La Brana 1, a 7,000-year-old individual from the La Brana-Arintero site in Leon, Spain. His approximate date of death was 7,150 BCE, which is close to that of La Brana 1. La Brana 1 had dark skin and blue eyes just as Cheddar Man and it carried the very rare Y-DNA haplogroup C6-V20, a low-frequency European clade of haplogroup C. Cheddar Man was determined to have belonged to haplogroup U5 and La Brana 1 belonged to mtDNA haplogroup U5b2c1 (Olalde et al. 2014). Just like La Brana 1, Cheddar Man may also have carried Y-DNA haplogroup C6, which explains his darker skin pigmentation compared to modern Europeans. Haplogroup C is a known Asiatic haplogroup and the first Briton may have been genetically half Asian. Haplogroup C reaches its highest frequencies among the indigenous populations of Mongolia, the Russian Far East, Polynesia, and Australia. Cheddar Man's paternal genetic heritage, haplogroup C6-V20, is also called haplogroup C1a2 (V20). C1a is extremely rare worldwide but it has been found mainly among individuals native to Japan (0.3%) or Europe (0.5%) and among Upper Paleolithic Europeans (i.e. La Braña 1).
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Post by Admin on Feb 10, 2018 18:59:11 GMT
The number of raw reads that aligned to the rCRS was 399,350. After applying the same processing steps described above for the autosomal portion of the genome, we kept 19,265 unique mtDNA reads with an average length of 78 bp, representing a depth of coverage of 91x for the mitochocondrial genome. The fact that the mtDNA reads are longer than their autosomal counterparts, confirms the observation in17 that mitochondrial DNA degrades at a slower rate. The La Braña 1 mtDNA haplogroup was previously classified as U5b2c12. Thus, we called an mtDNA consensus sequence and checked whether it could be assigned to this haplogroup again, using HaploGrep19 and Phylotree version 15. The consensus sequence displayed all the mutations expected for haplogroup U5b2c1. Next, to assess the presence of putative modern contamination in the sequenced reads, we calculated the proportion of sequences not matching the La Braña 1 consensus base in every position defining the haplogroup U5b2c1 (Table S4). For the 17 positions analyzed, 1.69% (0.75% - 2.67%, 95% C.I.) of the reads did not match La Braña 1 consensus haplogroup. The percentage of contamination provided here is an upper limit, as some of the discordant reads could be a consequence of heteroplasmic sites, nuclear-mitochondrial sequences (numts), sequencing errors, or DNA damage. In fact, 82% of these discordant reads display either a C to T change, or a G to A change, both characteristic misincorporations of ancient DNA. C is thought to be a consequence of a single out of Africa migration through Southern Asia, followed by a northward migration that eventually reached Siberia and the Americas 32. The fact that we found ancestral alleles in mutations defining C1, C2, C3 and C4 (Table S9), together with their actual phylogeographic distribution restricted to Asia, Oceania and the Americas suggests that our individual does not belong to any of these branches. Rather, a new branch within haplogroup C (C6, originally named C7) has recently been identified in several men from Southern Europe, suggesting this could be an ancient European clade33. Importantly, mutation V20 showed one read with the derived allele (A), which points to C6 as the most probable sub-clade for La Braña 1 sample. It could also be possible that this G to A mutation is a result of DNA damage. Other less likely haplogroup affiliations are C* and C5 (no read covered SNP M356), both found mainly in present-day India. Besides the V20 mutation, four other positions could have potentially been assigned wrongly due to the presence of DNA damage. However, their allele state is phylogenetically coherent with the rest of the SNPs studied. The precise affiliation of La Braña 1 in the Y-chromosome phylogeny could be better determined in the future with more data and increased genomic coverage.
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Post by Admin on Feb 12, 2018 18:43:24 GMT
Pigmentation In order to further investigate the pigmentation phenotype in this Mesolithic sample, we determined the ancestral/derived state in a set of additional pigmentation genes described to have a role in extant Europeans’ phenotype55,56. The coverage in La Braña 1 is stated for each SNP, ranging from 1x to 12x (Table S21). The low coverage in some of these SNPs can underestimate the heterozygosity and also can be subjected to potential confounding effects from post-mortem DNA damage. La Braña 1 shows ancestral alleles in several of them, including TYR, ASIP and MC1R. Interestingly, HERC2/OCA2 SNPs related to eye color on chromosome 15 (rs4778241, rs1129038, rs12593929, rs12913832, rs7183877, rs3935591, rs7170852, rs2238289, rs3940272, rs8028689, rs2240203, rs11631797, rs916977)57 consistently displayed a haplotype that is highly associated with blue eye color (Table S21). Furthermore, using the alleles present in La Braña 1 for the six most informative SNPs for eye color prediction58 and for other SNPs associated to hair color, the HIrisPlex model59 was applied (Table S22). We obtained a probability of 0.780 and 0.202 for having black and brown hair respectively. Regarding the eye color prediction, no data could be recovered for SNP rs12896399. Thus, accounting for the three possible genotypes in this SNP, we obtained a probability range of 0.706-0.458, 0.214-0.117 and 0.328-0.177 for blue, intermediate and brown color respectively. If it can be confirmed that La Braña 1 had blue eyes with the genotyping of the SNP rs12896399, it would be so far the oldest known individual carrying this trait. The combination of seven SNPs has also been shown to be useful in the prediction of “not-dark” and “not white” skin color in a global human sample60. However, some of these SNPs are not variable between Asians and Europeans and thus, its usefulness for skin color prediction in an ancient, European-specific genetic background is debatable. Moreover, the model, developed for forensics purposes, is based on the number of these SNPs present in a particular individual. La Braña 1 has the non-dark allele in rs6119471 (two copies), rs12913832 (two copies) and rs12203592 (one copy). Extended Data Figure 3: Genetic affinities of the La Braña 1 genome. Regarding the final phenotypic effect of each of these pigmentation genes, a semi-quantitative assessment of different functional studies classifies both SLC45A2 and SLC24A5 with the strongest effects in Europeans; MC1R, KITLG, IRF4 with medium effects and ASIP, OCA2, TYR and TYRP1 with weak effect55. All these genes show alleles that are present in high frequencies in Europeans but absent of rare in Africans; numerous association and functional studies have shown they play a role in light skin color in Europeans influencing the melanin synthesis, either as a membrane transporters (SLC45A2, SLC24A5, OCA2), growth factor (KITLG), melanogenic enzymes (TYR, TYRP1), G-protein coupled receptor (MC1R) or MC1R antagonist protein (ASIP). The only derived alleles found in La Braña 1 are present in IRF4 and two of the weak-effect genes, TYRP1 and ASIP. Interestingly, one of the SNPs (rs1408799) is basically associated to blue eye color in Europeans55. This is again in agreement with the prediction of dark skin pigmentation and non-brown eyes in this particular individual. The existence of many association studies on pigmentation and the understanding of the biochemical pathways involved in the melanosomes indicate that any new discovery on gene pigmentation will represent a very minor proportion of the observed phenotypic variation. As a conclusion, it is very difficult to ascertain the precise skin pigmentation phenotype of La Braña 1 individual from the comparison with modern human populations because the two critical pigmentation SNPs (at SLC45A2 and SLC24A5 genes) are essentially fixed in extant Europeans. Although some neighbouring populations such as Middle Easterns or North Africans can carry these ancestral alleles, their general genetic background is still quite different from that of modern Europeans and especially from Northern Europeans, to which La Braña 1 displays clear affinities. It is likely that La Braña 1 represents a unique phenotype that is no longer present in modern Europeans.
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Post by Admin on Feb 13, 2018 18:58:31 GMT
Extended Data Figure 8: Neighbouring variants for three diagnostic SNPs related to immunity. Immunity Pathogens are expected to have shaped the human genome as a result of selective pressures acting upon genes involved in host resistance and immunity response. The intimate contact with domesticated animals during the Neolithic is believed to have increased considerable the zoonotic infections (that is, the transmission of specific infectious diseases from an animal to humans). Indeed, it is believed that a large number of the common modern infections encountered in humans are zoonotic post-Neolithic events61. Several genome-wide scans for positive selection studies have detected different genes that could be involved in the Neolithic remodeling of the human immune system62. Due to the inherent difficulties of detecting recent positive selective events, some of these genetic targets have not been replicated in all studies; however, they represent instances of significantly large allele frequency differences between Europeans and the rest of the world populations. Extended Data Figure 1: Alignment and coverage statistics of the La Braña 1 genome. We have determined the ancestral/derived allele at the La Braña 1 Mesolithic genome in several genes that fulfill the following criteria: they show evidence of positive selection in European populations and they harbour polymorphisms shown to influence susceptibility to infections in European populations63–68 (Table S23). In total, we ascertained 63 SNPs from 40 genes. For several of these genes it has been argued that selective events driven by migration patterns and local infections have represented an important factor shaping the modern-day representation in European populations69. Nevertheless, the precise role of each gene in a general picture in relation to the possible zoonosis at the Neolithic is still not well understood. The assessment of these polymorphisms shows that a significant number of these genes present derived variant. The presence of the inactive CASP12 variant in the La Braña 1 individual support the earlier hypothesis of a pre-Neolithic origin for the spread and fixation of this mutation70,71. These genes encode proteins that are pattern-recognition receptors (TLR1, TLR3, TLR8, CD14, LGP2 and IFIH1), intracellular adaptor molecules (LRRK2), cytokines or cytokine modulators (SOCS2, TOLLIP, IFNG, CASP12, IL-29, TGFB2), chemokine and chemokine receptors (CCL18) and effector molecules (NOS2A), all with central roles in the host defense against major groups of viral or bacterial pathogens. Indeed, the fundamental role played by these genes in innate immune host defense and protection against major infectious diseases (e.g. sepsis), may explain the advent of protective genotypes in European populations independent and anterior to the spread of zoonotic infections due to domesticated animals. In line with this, the La Braña 1 individual carries the heterozygous haplotype at Mal/TIRAP gene that has been described as protective to a broad range of infections such as pneumococcal infection, bacteremia, malaria and tuberculosis72. The pre-Neolithic presence of these major infections (including malaria, known to have been present in the Southern part of the continent) in Europe is likely to have driven this pattern. Extended Data Figure 2: Damage pattern of La Braña 1 sequenced reads. In addition to the group of genes that show the presence of the derived protective allele in the La Braña 1 individual, other genes show however the presence of ancient variants. Important examples are SH2B3, that has been reported a strong recent selective event73. The derived allele that has been demonstrated to induce a stronger antibacterial immune response is absent in the La Braña 1 individual. The ancient allele is also present for the TLR6 gene, in which the derived variant has been suggested to protect against colonization and infection with lung pathogens74,75. The ancient haplotype is present for the well-known Asp299Gly and Thr399Ile TLR4 polymorphisms, although the impact of these gene variants on susceptibility to infections in more controversial76. CCR5delta32 polymorphism has been suggested to be selected in Europeans by either plague or smallpox77. Only one read of the gene was available in the La Braña 1 individual, nevertheless showing the absence of the deletion. In conclusion, the genotype in several important immune genes in the La Braña 1 individual shows that protective derived alleles present in extant Europeans have occurred before the Neolithic period for several important genes that have broad immune effects for bacterial and viral infections. Nevertheless, protective variants in several other immune genes are not present in this Mesolithic individual, arguing for a mixed picture of pre- and post-Neolithic events shaping the current immune system of Europeans.
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