Ancestry com suppresses the legacy of the Neanderthals
Quick notes on 14 recently read articles - not prepared in a generally understandable way, not proofread and in this form probably only useful to myself. 🙂 The whole thing gets messed up in the last part of the book, in which I chronologically treat the evolution of our immune system.
Gibbons A. (2014): Neandertals and moderns made imperfect mates. Science 343, January 31, 2014 (News on the work of Sankararaman et al. 2014, see below, and Vernot & Akey 2014)
Vernot & Akey only compared modern human genomes from the 1000 Genomes Project and drew conclusions about Neanderthal crossbreeding; Sankararaman et al. also included Neanderthal genome sequence. Neanderthals left traces (keratin) in their skin, nails and hair; Descendants of the hybrids were less fertile than "pure" modern humans.
Neanderthal version of the keratin function gene in over 60% of 1004 East Asian and European genomes. Keratin makes skin waterproof, blocks pathogens, makes skin sensitive to heat and cold -> adaptation to colder habitats?
Neanderthal alleles, which increase the risk of diseases like lupus, Crohn's disease, etc., may not have harmed Neanderthals, but they did not fit well with the new context in modern humans.
More Neanderthal alleles -> skin color.
In all examined modern human genomes together 20 or 30% of the Neanderthal genome was found; in an individual 1-3% of the genome is Neanderthal. Intersection about 60,000 years ago.
About 20 regions of the human genome do not contain any Neanderthal DNA -> negative selection because of the reproductive disadvantages of the hybrids. Women tend to remain fertile because of the double X chromosome -> We are now investigating whether we have taken over more DNA from female than from male Neanderthals. (What is probably meant is the gender of the mixed children, not the pure Neanderthal parent - it makes no difference as long as male hybrids with Neanderthal X and modern Y are just as (un) fertile as male hybrids with modern X and Neanderthal Y. )
Sankararaman S. et al. (2014): The genomic landscape of Neanderthal ancestry in present-day humans. nature, doi: 10.1038 / nature12961
Comparison between Neanderthal genomes and 1004 modern genomes (including 176 Yoruba, presumably Neanderthal free) -> Neanderthal haplotypes derived. Regions with many Neanderthal alleles contain many genes that influence keratin filaments -> skin and hair -> makes it easier for modern people to adapt to the environment outside of Africa? Large Neanderthal allele-free "deserts" in the human genome, e.g. B. on the X chromosome, which contains many male fertility genes; only partially explained by the small population size shortly after crossing -> negative selection, possibly. because Neanderthal alleles reduced fertility in the genome context of modern humans.
Haplotype lengths -> crossing about 2000 generations ago, i.e. 37,000-86,000 years ago. Neanderthal proportion in individual genomes: today an average of 1.15% in Europe, 1.38% in East Asia; shortly after crossing over 3% (derived from the proportion in "non-desert regions"). Larger proportion in East Asians, possibly due to smaller populations over a long period of time than in Europe -> negative selection less effective. Probable Neanderthal proportion at individual gene locations: up to 62% in East Asian, up to 64% in European populations. In some of these regions signs of positive selection, in others negative selection.
Alleles from Neanderthals influence the risk of SLE / lupus, primary biliary cirrhosis (both: transportin-3), Crohn's disease (chromosome 10: zinc finger protein 365, chromosome 12: gene unknown?), IL-18 level (regulator of the innate and acquired immunity), type 2 diabetes, smoking, and blind spot size.
Although only about five times more time had passed since the split between Neanderthals and ancestors of modern humans than today since the split between Europeans and West Africans, the fertility of the hybrids was probably greatly reduced due to snowball effects (Dobzhansky-Müller incompatibilities) .
Examiner K. et al. (2014): The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, doi: 10.1038 / nature12886
High-quality genome sequence of a Neanderthal woman from the Denisova Cave in the Altai Mountains, Siberia - obtained from a toe bone from a layer around 50,000 years old. The finger bone, from which the preliminary genome sequence of the Denisova human was determined, was also found in the same cave, but in a slightly younger layer. Comparison of several Neanderthal genomes (also from the Caucasus and Croatia, see map Fig. 1), the Denisova human genome and 25 modern human genomes -> model of cross-breeding events between modern humans, Denisova, Neanderthals and an unknown hominid (Fig. 8th). Splitting of modern humans and Neanderthals / Denisova ancestors before 553,000-589,000 or (according to the 2nd method) 550,000-765,000 years ago, splitting of Neanderthals and Denisova before 381,000 or (according to the 2nd method) 445,000-473,000 years. Altai Neanderthal woman: extremely homozygous genome -> On the one hand, the parents were as closely related as half-siblings (with a common mother, not father - to be recognized by X chromosome homozygosity). On the other hand, the entire subpopulation from which the parents came was small and relatively closely related. Ancestors of modern humans, Neanderthals and Denisova humans all went through a bottleneck about 1 million years ago; thereafter, populations of the ancestors of modern humans grew while the other two populations declined.
Gene flow: 1.5-2.1% of the genome of non-African modern humans are from Neanderthals. This Neanderthal genome is more similar to the Caucasus Neanderthal genome than the Altai or Croatian Neanderthal genomes. Denisova genome mainly in Melanesians (Papua New Guinea and Australia, about 5%) and mainland Asians (e.g. Han Chinese) and Native Americans (about 0.2%). At best, very little Denisova admixtures in Sardinian and French-Basque genomes. The proportion of Neanderthals in Asians and Indians is also greater than in Europeans. The alternative hypothesis that the archaic elements in the genome of modern humans originate from a split in the period before Out of Africa is rejected on the basis of the current data situation.
Splitting Altai Neanderthals and "gene donors" Neanderthals 77,000-114,000 years ago, splitting Denisova genome and "gene donors" Denisova humans 276,000-403,000 years ago. Denisova population is larger, more diverse and / or more subdivided than the Neanderthal population, which has little diversity both in the nuclear genome and in its mtDNA. Gene flow from Neanderthals to Denisova humans: at least 0.5% of the Denisova genome; Similarity with the Altai Neanderthals is greater than with the Croatian or Caucasus Neanderthals. A gene flow Denisova-human -> Neanderthals, modern human -> Neanderthals or modern human -> Denisova-human cannot be detected (because of the age of the archaic genomes - that does not mean that there was no gene flow in the opposite direction!). Also possible gene flow from unknown hominini (perhaps H. erectus), which split off from ancestors of Neanderthals, Denisovans and modern humans approximately 0.9-1.4 million years ago or 1.1-4 million years ago the Denisova people. H. erectus began to spread from Africa about 1.8 million years ago.
Particularly strong influx of the Neanderthal HLA region (immune system) and CRISP gene clusters (sperm production; both on chromosome 6) into the Denisova genome, typically a few decades before the death of the Altai Neanderthal. Analogous to HLA allele influx of Neanderthals -> modern humans, see Abi-Rached 2011!
Catalog of the differences between most of 1094 genomes of modern humans and the genomes of archaic humans and great apes. Relatively few genes / proteins, some of which are involved in brain development.
Jones J. C. & G. J. Freeman (2013): Costimulatory genes: hotspots of conflict between defense and autoimmunity. Immunity 38, doi: 10.1016 / j.immuni.2013.06.008 (news about Forni et al., See below)
Forni et al. have examined the selection of 15 important co-stimulation genes, the products of which are located in the membranes of antigen-presenting cells and T-cells, bind to each other in pairs and have thus been regulating the activity of T-cells in mammals for 175 million years. -> Increased autoimmunity risk is the downside of improved pathogen control by the immune system.
For a few amino acids in 9 of the 15 molecules, dN / dS> 1 indicates a positive selection (accumulation of significantly more nonsynonymous than synonymous base exchange mutations in the DNA). In the proteins, these hotspots are located partly in the transmembrane domain, partly in the IgV or IgC domain, partly in the stalk, partly in extra- or inner-cell death domains (-> apoptosis). The selection may have influenced the ligand binding strength and thus the importance of the T cell regulatory molecules in different ways.
Natural selection has influenced the genetic diversity of the genes for CD80, PD-L1, TIM-3, CD40LG, FAS, and PD-1 in humans for the past 250,000 years. Clearly, however, only in non-coding sequences of the human genome, which, however, can influence the level of expression of the T cell regulating molecules. (There are only very few amino acid exchanges in the human genome that have been positively selected in the last 250,000 years - probably fewer than 340. The vast majority of the selected mutations occurred in non-coding DNA segments that influence the expression of genes.)
Geographical distribution of the selected variants compared with selection pressure from pathogen diversity (viruses, bacteria, protozoa, worms) -> Suspected expression-regulating variants of PD-L1, FASLG and CD40LG are geographically limited and correlate with pathogen diversity.
With PD-1 signs of gene flow from Asian H. sapiens to Neanderthals (sic, not the other way around!). The alleles were selected positively in Neanderthals because of the similar pathogen pressure.
In 7 of 13 disease-associated SNPs in the genes of the T cell regulatory molecules, the frequency of the risk alleles correlates regionally with the diversity of at least one of the four pathogen groups. Six of these 7 SNPs are associated with autoimmune diseases. The risk alleles probably convey protection against the pathogens and were therefore selected positively.
Forni D. et al. (2013): A 175 million year history of T cell regulatory molecules reveals widespread selection, with adaptive evolution of disease alleles. Immunity 38, doi: 10.1016 / j.immuni.2013.04.008
Abstract: T-cell activation important for defense and self-tolerance. 9 genes involved in T-cell activation or regulation of the T-cell response evolved adaptively in mammals. Human: local positive selection in FASLG, CD40LG, HAVCR2, worldwide positive selection in FAS and ICOSLG. Gene transfer H. sapiens -> Neanderthals. A polymorphism that influences risk of Crohn's disease has arisen from selection pressure from bacteria and influences the expression of ICOSLG in response to a bacterial superantigen. -> The preservation of risk alleles for autoimmune diseases is based on adaptation to infections.
Introduction: Co-stimulation molecules of the B7 family are crucial for T-cell activation and thus for defense and homeostasis. Best characterized: B7-1 = CD80 and B7-2 = CD86 on APCs that either bind to CD28 (-> activation) or to CTLA4 (-> dampening of the immune response) on T cells. CD274 = PD-1 binds either to PDCD1 (-> tolerance induction or destruction of autoreactive T cells) or PDCD1LG2 = PD-L2 on non-T cells (-> T cell reaction suppressed). Binding of FAS to FASL and of LGALS9 to TIM-3 = HAVCR2 -> apoptosis. TIM family is involved in the inhibition of Th1 immune responses; instead, in LGALS9: TIM-3 binding, naive T cells become Tregs. ICOS: ICOSL -> regulation of cell proliferation. CD40: CD40L -> lymphocyte activation and regulation of B-cell function. Because of the crucial function of these T-cell regulating molecules in T-cell reactions, they are constantly being tricked by pathogens -> permanent conflict -> genetic variants can be positively selected, but they can also lead to immunodeficiency, autoimmune diseases and chronic inflammation.
Results, section “natural selection shaped allele frequencies at disease variants”: 20 variants in the previously identified genes of the T cell regulating molecules found using GWAS; in 7 of them, the regional frequency of the variants (Europeans, Yoruba, Asians) correlates with the diversity of at least one pathogen type (viruses, bacteria, protozoa, worms); 6 of them associated with autoimmune diseases: rs231735 T (between the CD28 and CTLA4 genes) with rheumatoid arthritis, rs1024161 T (also between the CD28 and CTLA4 genes) with Graves’s disease and alopecia areata, rs762421 G (next to ICOSLG) with Crohn’s disease, rs (Intron or UTR in CD86) with multiple sclerosis, rs859637 A (next to FASLG) with celiac disease and rs9286879 G (next to FASLG) also with Crohn's disease. (The letter is the base in the risk allele.)
In some risk variants, there are signs of balancing selection (greater nucleotide diversity than would be expected under the assumption of neutrality for the respective divergence). Experiment: ICOSLG mRNA in peripheral blood mononuclear cells from 18 healthy subjects with 3 rs762421 genotypes after staphylococcal enterotoxin treatment (bacterial superantigen) with a homozygous presence of the risk allele induced 2.5 times more than with homozygosity for a non-risk allele. Evidence that the risk alleles provide better protection against infections.
Risk allele for IgA deficiency (the 7th variant), on the other hand, is more common where the pathogen pressure is low. Affected people more susceptible to bacterial infections.
Discussion: 9 of 15 genes examined have undergone positive diversifying selection - some of them only in humans, whereby autoimmune risk alleles have spread. Pathogens develop e.g. T. strategies that change the transcription of these genes, or molecules that bind directly to the gene products and impair their function; In addition, viruses use T-cell regulator molecules (especially IgV domains) as gateways.
Certain new amino acids in TIM-3, C D80 and CD274 may have been selected to avoid virus exploitation. In the case of CD86, it has been proven that viruses have contributed to diversification: MIR2 ubiquitinase of Kaposi's sarcoma herpes virus = human herpes virus 8 binds to CD86; proteins that are similar to other viruses are known.
All adaptative changes in T cell regulatory molecules in humans reside in non-coding sequences. TIM-3 is likely to be attacked by a number of pathogens in order to weaken the immune system: e.g. HIV-1 and hepatitis C -> T cell exhaustion. CD274 is also upregulated by Helicobacter pylori, mycobacteria and HIV-1, which weakens or even switches off the immune system. Selected CD274 and FASLG variants differ geographically, correlate with pathogen diversity.
PDCD1: Observations do not match the gene flow from Neanderthals to modern humans, better the opposite direction. Balancing selection -> two very old haplotypes obtained in Asia (TMRCA >> 37,000-86,000 years, assumed time window of hybridization), one of which got into the Neanderthals through hybridization.
Temme S. et al. (2014): A novel family of human leukocyte antigen class II receptors may have its origin in archaic human species. JBC 289, doi: 10.1074 / jbc.M113.515767
Good job on why certain mixed isotype HLA class II heterodimers are stable and others are not. Chaperone role of the invariant chain (Ii = CD74). Identified family of DPβ chains that form functional antigen presenting complexes with DRα. The two crucial DPβ sequences (Lys-69 and GGPM 84-87) control the stabilizing maturation (N-glycosylation) of the heterodimers in the Golgi apparatus. They occur in the allele DPB1 * 0401, which is rare in sub-Saharan Africa (11%) and common in Europe (68%).
This allele also occurs in the Neanderthal genome and could have been taken over by the Neanderthals after Out-of-Africa (crossbreeding) and then spread because of a selection advantage (Neanderthal adaptation to Eurasian pathogens). A whole DPβ family may have developed from this in modern humans. However, it is difficult to provide evidence, as Lys-69 and GGPM 84-87 also occur separately in other HLA alleles and could have come together simply through recombination during / after Out-of-Africa. Here, too, reference to Abi-Rached 2011.
Mendez F. L. et al. (2012) Neandertal origin of genetic variation at the cluster of OAS immunity genes. Mol. Biol. Evol. 30/4, doi: 10.1093 / molbev / mst004
A haplotype of the OAS gene cluster on our chromosome 12, which is around 185 kilobases long and is almost completely restricted to Eurasia, presumably comes from Neanderthals; crossed about 124,000 years ago. The frequency of the haplotype does not speak against selection neutrality. After STAT2, this is the second locus in our genome that presumably has haplotypes from both Neanderthals and Denisovans that were crossed separately. The authors reject the alternative hypothesis that such sequence similarities can be traced back to an ancient polymorphism in Africa on the basis of statistical analyzes.
OAS region in our genome: bounded by 2 recombination hotspots; includes genes OAS1, OAS2, OAS3; 8 haplotypes, one of which (R) almost completely matches the sequence in Neanderthals. (The oligoadenylate synthetases count 1-3 are used to fight viruses by the innate immune system; the enzymes are induced by interferons and in turn activate the enzyme RNAse L, which inhibits virus replication.) The crossed by Neanderthals and crossed by Denisovans Blocks overlap heavily. Estimation of the time of crossbreeding based on the deviations between the Neanderthals and the derived haplotype R and comparison with the chimpanzee genome (split 6 million years ago) -> about 124,000 years, i.e. significantly younger than split Neanderthals / ancestors of modern humans (about 300,000 years ). In Europe, the last common ancestor of the polymorphic haplotype R appears to have existed around 43,000 years ago.
Haplotype R contains 6 polymorphic sites that affect the OAS protein sequences. One of them is associated with different symptoms in north-eastern Europe in viral, tick-borne encephalitis. R haplotype: OAS2 8 amino acids longer than all other derived haplotypes. Functional consequence of the other 5 polymorphisms coming from Neanderthals unclear.
Haplotype R is hardly represented in sub-Saharan Africa. The striking geographical distribution of the haplotypes in 3 regions (Africa, Eurasia, Melanesia) can be attributed to balanced polymorphism (balancing selection) indicate at the OAS1 gene location (similar to sickle cell anemia / malaria); but it can also be selection-neutral. Reference to Abi-Rached 2011: Further studies will show whether immune system gene locations are particularly susceptible to the effects of archaic crossbreeding.
Mendez F. L. et al. (2012): A haplotype at STAT2 introgressed from Neanderthals and serves as a candidate of positive selection in Papua New Guinea. The American Journal of Human genetics 91, doi: 10.1016 / j.ajhg.2012.06.015
Abstract: So far (2012) no clear evidence of adaptative introgression Neanderthals -> modern humans. Congenital immune system STAT2: Haplotype N, which is practically non-existent in Sub-Saharan Africa, in Eurasia in around 5% of people and in Melanesia in 54%, has a sequence that is very similar to the equivalent in the Neanderthal genome and shares a common original sequence goes back about 80,000 years ago. Neutrality test: It is very unlikely that a variant of N in Melanesia was caused by genetic drift alone. The exact goal of positive selection is still unknown; good candidates are the nonsynonymous mutations in ERBB3, ESYT1 or STAT2.
Cladogram with 13th STAT2-Haplotyopes, determined from sequences of 90 people: Fig. 2. Four clades: S (San), D (Denisova), N (Neanderthals), M (modern humans). S occurs (exclusively) in 35% of the San, D (exclusively) in 9% of the Papuans, N in 59% of the Papuans and in 9% of the Basques. Subclade Ma is restricted to sub-Saharan Africa and occurs there in 65% to 75% of the populations. Subclade Mb is the most common worldwide (48%) and is particularly well represented among the Han (97%) and the Basques (91%).
Discussion: Summary of the arguments for hybridization and direction of gene flow at STAT2-Genort (match N and Neanderthal sequence, lack of N in sub-Saharan Africa, great length of N in Europe and even more so in Asia and Melanesia, which does not fit the split between Neanderthals and modern humans 600 million years ago, but on the primordial sequence about 160 million years ago; direction: length LD in modern humans). ERBB3 is a cell surface receptor that is involved in cell growth, cell survival, differentiation, and suppression of apoptosis. ESYT1: ubiquitous transmembrane protein that is very strongly expressed during the differentiation of fibroblasts into adipocytes. STAT2: Key role in one of the JAK-STAT signaling pathways (interferon signaling system).
A high proportion of the haplotype N in Melanesia suggests positive selection, e.g. B. by pathogen pressure. Exact destination unclear. The fact that N is frequent but far from being fixed in Melanesia (i.e. found in 100% of the population) can have three reasons: insufficient time since the late start of positive selection (after a long neutral phase since hybridization), weak selection coefficient or balancing selection. Combinations are also possible.
Abi-Rached L. et al. (2011): The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 334, doi: 10.1126 / science.1209202
Was there positive selection of the DNA crossed into modern humans by Neanderthals and Denisovans? Authors think: yes. Analysis of highly polymorphic, strongly balancing selection exposed components of HLA class I (immune system) -> Modern humans took over allele HLA-B * 73 in West Asia from Denisova humans. Further archaic HLA haplotypes identified that were crossed into modern Eurasian and oceanic populations. Some code for unique or strong ligands of the receptors of natural killer cells and now make up over half of the HLA alleles of modern Eurasians; later they also came to America.
HLA-A, -B and -C (on chromosome 6p21.3) belong to MHC class I, are ligands for T-cell and NK-cell receptors. Maintaining great diversity in these proteins is important for long-term survival of human populations. Hence strong multi-allelic balancing selection, which, together with recombination, ensures a sufficiently large variety, with the quantitative proportions of the alleles and haplotypes being influenced by the local environmental conditions (especially pathogen pressure) - similar to the balancing selection in the moth or sickle cell anemia.
Among the more than 2000 HLA-B alleles in humans, HLA-B * 73: 01 has a special position: It is closely related to some MHC-B alleles of chimpanzees and gorillas. Its predecessor separated from the MHC-BI about 16 million years ago - long before the split between man and gorilla - and it is the only representative of the MHC-BII group in humans (apart from the pygmies). Despite these archaic features, its sequence is homogeneous - an indication of a relatively young crossbreeding. It is common in Western Asia (Iran / Turkmenistan) and rare in the rest of the world. Is in coupling imbalance with HLA-C * 15: 05, which also has a focus on West Asia, and is absent from the Khoisan / Pygmy populations, which probably split off from the other African populations before Out-of-Africa and are very unique have old mt, Y chromosome and MHC B1 variants. Data suggest that B * 73 in West Asia was crossed from archaic people into modern people and then spread - also back to Africa.
HLA class I characterized by a Denisova human and three Neanderthals. Since Denisovans and modern humans separated more than 250,000 years ago (around 10,000 generations), great similarities in HLA haplotype combinations between them are probably not archaic holdovers (which would have long since disintegrated in the rapidly evolving MHC), but evidence of more recent crossbreeding . Denisova crossbreeds have primarily shaped the HLA system of the Asians and Native Americans.
The three Vindija Neanderthals (Croatia) have quite similar genomes. Also applies to HLA class I: all the same alleles, probably belonged to the same small and isolated group. Neanderthal HLA allele combinations / haplotypes are most common in modern Eurasians and are absent in Africa -> crossbreeding in Eurasia. Haplotypes with B * 07, B * 51, C * 07: 02 and C * 16: 02 probably come completely from the Neanderthals. Distribution in Eurasia wider than Denisova-DNA; Peaks in different areas of Eurasia.
HLA class I shows higher recombination rates in Europe and Asia than in Africa, which speaks for greater proportions of archaic alleles, because these destroy coupling groups (reduced LD). Apparently A * 11, A * 26, two A * 02 groups, A * 24: 02 and A * 31: 01 were crossed. Derived from the combined frequencies of these 6 alleles:> 50% of the European,> 70% of the Asian and> 95% of the Papua New Guinea HLA-A originate from archaic crosses. Cross-breeding is estimated at 1-6% genome-wide -> positive selection in the game. Presumably this also applies to other polymorphic immune system genes such as KIR in NK cells.
Modern people encountered archaic people at Out-of-Africa, whose immune systems were better adapted to local pathogens after more than 200,000 years of residence. For small hiking groups, crossbreeding was important in order to regenerate HLA diversity according to population size bottleneck and to acquire new variants that were adapted to the local pathogens. Example: Archaic allotype HLA-A * 11 is common in modern Asian populations, offers T-cell-mediated protection against some Epstein-Barr virus strains and, together with EBV peptide, is one of only two HLA ligands for the NK - Cell receptor KIR3SL2 and strongest ligand for another KIR. -> Adaptive crossing of HLA alleles, whose products KIR ligands are probably driven by their role in the control of NK cells, which are important for immune defense and reproduction. Other alleles, the products of which are not KIR ligands, arguably driven by their role in T cell control. (Abbn: 1 B, C, F)
Fernandez Vina M.A. et al. (2012): Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations. Phil. Trans. R. Soc. B 367, doi: 10.1098 / rstb.2011.0320
Basic explanations on the structure of HLA, alleles, haplotypes, coupling groups, etc .; Inefficient except for the statement that the HLA system has been under strong selection for millions of years and that in small founder populations (according to the bottleneck) every newly added (crossed or mutated) allele should be advantageous because it increases the diversity in the population and thus also in the individuals offers better chances against diverse / new pathogens through heterozygosity. This sometimes leads to genetic gaps between 2 related populations that are larger than their geographic distance suggests.
Ding Q. et al. (2013): Neanderthal introgression at chromosome 3p21.31 was under positive natural selection in East Asians. Mo. Biol. Evol. 31/3, doi: 10.1093 / molbev / mst260
Also: Caspermeyer J., Sunlight adaptation region of Neanderthal genome found in up to 65% of modern East Asian population
Accumulation of Neanderthal DNA in a 200 kb region on chromosome 3, which contains 18 genes, some of which, like Hyal2, have to do with adaptation to UV light. Geographical distribution of the Neanderthal alleles suggests that UV light gene variants that were lost during Out-of-Africa found their way back into the genome of modern humans via the Neanderthals. Whether or not East Asians contain more Neanderthal DNA overall is something that authors consider to be debatable, but it is true with Hyal2. 45,000-5000 years ago the effective population size of this Neanderthal gene region increased steadily, 5000-3000 years ago the growth rate increased -> probably an overall “population explosion”.
Hyaluronoglucosaminidases are involved in the response of cells to UV-B light. Haplotypes originating from Neanderthals: practically never found in Africa, little in Europe, relatively common in Central America, detected in 49.4% of a Japanese population and 66.5% of a southern Han Chinese population (map Fig. 3). The target of the selection seems to be rs12488402-T, one of 4 nonsynonymous single nucleotide polymorphisms (SNPs) in strong coupling disequilibrium (LD) with rs12488302.
Immigrant haplotypes separated from the ancestors of modern humans about 429,750 years ago and from the ancestors of the Altai Neanderthals (who lived about 50,000 years ago) about 34,840 years ago. The Neanderthal haplotypes merged about 45,000 years ago (crossbreeding); thereafter their spread increased; 5000-3500 years ago before the present, the growth rate of their effective population size increased, indicating explosive population growth. This observation can be explained either by population growth in the Neolithic or by positive selection (or a combination of both).
The 3p21.3 region contains a cluster of well-studied tumor suppressor genes, including HYAL2 and other genes from the HYAL region. HYAL2 breaks down hyaluronic acid. Hyaluronic acid metabolism is linked to tumor development; Naked mole rats are cancer resistant and have high molecular weight hyaluronan in their tissues.
Latitude gradient: the further south an Asian population, the greater the proportion of crossed haplotypes. Sunlight exposure could be a selection factor; but more data is required for receipt. Increased hyaluric acid metabolism after UV-B radiation. Expression level HYL2 influenced by UV-B; Direction still unclear (contradicting in-vitro test results). Exchange of the old allele G by crossed allele T -> isoleucine instead of leucine as the 418th amino acid in HYAL2. Increased prevalence of keloids Africa and Asia (especially Japan): decreased hyaluronic acid level demonstrated; higher risk perhaps due to polymorphism at rs35455589.
Ahmed M. & P. Liang (2013): Study of modern human ecolution via comparative analysis with the Neanderthal genome. GenomicsInform 11/4, doi: 10.5808 / GI.2013.11.4.230
Chimpanzee-human split 6 million years, upright gait for around 4 million years, emergence of Neanderthals from H. erectus around 400,000 years ago, emergence of modern humans from H. erectus around 200,000 years ago in East Africa; modern man began to emigrate from East Africa about 100,000 years ago. Neanderthals and modern humans could have met about 80,000 years ago and lived in certain areas for up to 10,000 years at the same time. (Attention, completely different numbers from e.g. Neves & Serva! On p. 233 it says: Evidence for the appearance of modern people in the Middle East already> 100,000 years ago; Neanderthals may have stayed until 50,000 years ago.) Neanderthals survived until before about 28,000 years ago, still lived in Europe, Western Asia and the Middle East towards the end. Up until about 50,000 years ago, Neanderthals were presumably as intelligent as modern humans, then in modern humans an explosion of creativity.
Neanderthal mtDNA bears no resemblance to that of modern humans. In Neanderthals, MC1R gene -> presumably red hair and light skin.
Most of the deviations in the human genome compared to Chimpanzee genomes emerged before the split between Neanderthals and modern humans. Only 78 non-synonymous base exchanges are fixed in the human genome, which are not found in Neanderthals. Only 5 genes with more than one change in coding region were found. Three of them expressed in skin, e.g. B. Melastatin gene -> Selection of skin physiology in modern humans? Regulatory / non-coding sequences: more innovations, probably heavily involved in brain development.
Overmann K. A. & F. L. Coolidge (2013): Human species and mating systems: Neandertal-Homo sapiens reproductive isolation and the archaeological and fossil records. JAS 91, doi: 10.4436 / JASS.91021
Comparison of chimpanzee bonobo hybridizations (in captivity) and the putative hybridizations of Neanderthals and modern humans. Reproductive isolation (RI) in primates can make crossbreeding asymmetrical. Doesn't have to be infertility; Behavior can also play a major role (violence between groups, xenophobia, acceptance of different partners / children, infanticide, ...)
Genome sequencing data are mainly interpreted as evidence of one-sided gene flow from Neanderthals to modern humans. (But see e.g. Forni et al. 2013, A 175 Million Year History of T Cell Regulatory Molecules Reveals Widespread Selection, with Adaptive Evolution of Disease Alleles!) Currat et al 2008: Introgressive genes normally flow from the in animals and plants local to the invasive species. Even a small contribution of the old-age Neanderthals to the modern human genome may have spread as the population of modern humans increased and that of the Neanderthals declined.
(Partial) infertility or a lower survival rate in male hybrids can explain why there is no gene flow in the Y chromosome. It is possible that only female children of Neanderthal fathers and “modern mothers” were fertile. Splitting Neanderthals / modern humans at most 500,000 years ago, maybe only 440,000-270,000 years ago. The mean time to sterility of hybrids in mammals is 2.0-4.0 million years. At that time, the two types of people are likely to have differed less than some populations today who have children together without any problems. Hence perhaps more cultural or social reasons for the extensive reproductive isolation: The different people rarely recognized each other as potential partners.
Chimpanzee Bonobo Model: The two species are the closest relatives of Neanderthals and modern humans. Are so close that they could be grouped into one species - just like the two human species. (Overmann and Coolidge actually assume that H. neanderthalensis was a species of its own; this is controversial.) Hybridization possible in both cases, since areas of distribution overlap; however, the Congo River as a barrier -> hybrids v. a. in prison. Differences in morphology and behavior are as large as in humans; Bonobos and H. sapiens pedomorphic / juvenile; Chimpanzees and H. neanderthalensis sexually mature faster and more robust. Chimpanzee-bonobo hybrids have intermediate appearance and behavior, normal life expectancy.Asymmetric gene flow due to postzygotic RI in macaque hybrids.
2013 were compared to modern humans. Neanderthals 9 non-synonymous substitutions found in genes that affect learning and memory.
Table 1: Intergroup violence and xenophobia of Neanderthals (who probably lived in small, isolated groups) should have reduced the likelihood of crossbreeding in both directions. Differentiating in foraging for food (H. sapiens: women individually or in groups of women foraging for food, men on the hunt; Neanderthals: mixed-sex hunting groups) could have increased the likelihood of mating between Neanderthal men and Sapiens women. Because of the different speed of maturation and different physical strength, pairings between Neanderthal men and Sapiens women could have been more likely than the other way round - e.g. B. because Sapiens men seemed too immature to Neanderthal women to be considered partners.
Table 2: Fitness of the hybrids: Hybrids that lived with H. sapiens could have had better chances of survival and reproduction with intermediate morphology. Hybrids that lived in Neanderthal groups may have had a worse chance of survival - e.g. B. because they grew up too slowly, had less muscle mass, etc.
Neves A. & M. Serva (2012): Extremely rare interbreeding events can explain Neandertal DNA in living humans. PLOS One 7/17, doi: 10.1371 / journal.pone.0047076
The simple model is overtaken by new Neanderthal sequence data, because it postulates z. B. about the same amount of Neanderthal DNA in all Eurasians - unlike the more complex model by Currat & Excoffier (2011), which fits the data better (more Neanderthal genome in Asians). But explains quite well why the lack of Neanderthal sequences in our mtDNA (and our Y chromosome DNA?) Does not speak against a Neanderthal crossbreeding, as can be seen in our core DNA. Location of hybridization: Middle East, e.g. B. Skhul and Kafzeh caves in Israel, where Neanderthals and African ancestors of modern humans coexisted for at least 130,000 years and used the caves alternately. Bar-Yosef compares this to a long football game. The model assumes neither strong sexual isolation nor a selection advantage for either of the two populations. Total population size if Neanderthals survive for at least 130,000 years: about 10,000.
Other unsorted links on the topic:
Neanderthal skin and hair: researchers identify which genes we inherited from our Ice Age cousins
Inner Neanderthal: Two studies demonstrate the extent of Neanderthal DNA that persists in modern human genomes
Resurrecting Surviving Neandertal Lineages from Modern Human Genomes
Ancient DNA reveals secrets of human history
Type 1 diabetes and the OAS gene cluster: association with splicing polymorphism or haplotype?
Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico
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