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Post by Admin on Sept 25, 2023 19:47:58 GMT
We carry DNA from extinct cousins like Neanderthals. Science is now revealing their genetic legacy
Neanderthals live on within us.
These ancient human cousins, and others called Denisovans, once lived alongside our early Homo sapiens ancestors. They mingled and had children. So some of who they were never went away — it’s in our genes. And science is starting to reveal just how much that shapes us.
Using the new and rapidly improving ability to piece together fragments of ancient DNA, scientists are finding that traits inherited from our ancient cousins are still with us now, affecting our fertility, our immune systems, even how our bodies handled the COVID-19 virus.
“We’re now carrying the genetic legacies and learning about what that means for our bodies and our health,” said Mary Prendergast, a Rice University archeologist.
In the past few months alone, researchers have linked Neanderthal DNA to a serious hand disease, the shape of people’s noses and various other human traits. They even inserted a gene carried by Neanderthals and Denisovans into mice to investigate its effects on biology, and found it gave them larger heads and an extra rib.
Much of the human journey remains a mystery. But Dr. Hugo Zeberg of the Karolinska Insitute in Sweden said new technologies, research and collaborations are helping scientists begin to answer the basic but cosmic questions: “Who are we? Where did we come from?”
And the answers point to a profound reality: We have far more in common with our extinct cousins than we ever thought.
NEANDERTHALS WITHIN US
Until recently, the genetic legacy from ancient humans was invisible because scientists were limited to what they could glean from the shape and size of bones. But there has been a steady stream of discoveries from ancient DNA, an area of study pioneered by Nobel Prize winner Svante Paabo who first pieced together a Neanderthal genome.
Advances in finding and interpreting ancient DNA have allowed them to see things like genetic changes over time to better adapt to environments or through random chance.
It’s even possible to figure out how much genetic material people from different regions carry from the ancient relatives our predecessors encountered.
Research shows some African populations have almost no Neanderthal DNA, while those from European or Asian backgrounds have 1% to 2%. Denisovan DNA is barely detectable in most parts of the world but makes up 4% to 6% of the DNA of people in Melanesia, which extends from New Guinea to the Fiji Islands.
That may not sound like much, but it adds up: Even though only 100,000 Neanderthals ever lived, “half of the Neanderthal genome is still around, in small pieces scattered around modern humans,” said Zeberg, who collaborates closely with Paabo.
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Post by Admin on Sept 26, 2023 21:11:25 GMT
It’s also enough to affect us in very real ways. Scientists don’t yet know the full extent, but they’re learning it can be both helpful and harmful. For example, Neanderthal DNA has been linked to auto-immune diseases like Graves’ disease and rheumatoid arthritis. When Homo sapiens came out of Africa, they had no immunity to diseases in Europe and Asia, but Neanderthals and Denisovans already living there did. “By interbreeding with them, we got a quick fix to our immune systems, which was good news 50,000 years ago,” said Chris Stringer, a human evolution researcher at the Natural History Museum in London. “The result today is, for some people, that our immune systems are oversensitive, and sometimes they turn on themselves.” Similarly, a gene associated with blood clotting believed to be passed down from Neanderthals in Eurasia may have been helpful in the “rough and tumble world of the Pleistocene,” said Rick Potts, director of the human origins program at the Smithsonian Institution. But today it can raise the risk of stroke for older adults. “For every benefit,” he said, “there are costs in evolution.” In 2020, research by Zeberg and Paabo found that a major genetic risk factor for severe COVID-19 is inherited from Neanderthals. “We compared it to the Neanderthal genome and it was a perfect match,” Zeberg said. “I kind of fell off my chair.” www.nature.com/articles/s41586-020-2818-3The next year, they found a set of DNA variants along a single chromosome inherited from Neanderthals had the opposite effect: protecting people from severe COVID. www.pnas.org/doi/10.1073/pnas.2026309118The list goes on: Research has linked Neanderthal genetic variants to skin and hair color, behavioral traits, skull shape and Type 2 diabetes. One study found that people who report feeling more pain than others are likely to carry a Neanderthal pain receptor. www.cell.com/current-biology/fulltext/S0960-9822(20)30861-7 Another found that a third of women in Europe inherited a Neanderthal receptor for the hormone progesterone, which is associated with increased fertility and fewer miscarriages. pubmed.ncbi.nlm.nih.gov/32437543/Much less is known about our genetic legacy from Denisovans – although some research has linked genes from them to fat metabolism and better adaptation to high altitudes. Maanasa Raghavan, a human genetics expert at the University of Chicago, said a stretch of Denisovan DNA has been found in Tibetans, who continue to live and thrive in low-oxygen environments today. Scientists have even found evidence of “ghost populations” — groups whose fossils have yet to be discovered — within modern humans’ genetic code. |
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Post by Admin on Sept 28, 2023 18:53:15 GMT
A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans
Summary
The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in ∼0.4% of present-day Britons, where they are associated with heightened pain sensitivity.
Results and Discussion
Neanderthals and their Asian relatives, Denisovans, evolved largely separately from the ancestors of present-day humans for about 500,000 years [2]. During that time, each group independently accumulated genetic changes that became frequent or fixed. However, late in their history, Neanderthals and Denisovans mixed with modern humans, which resulted in many genetic variants from Neanderthals and Denisovans being present in humans today [3, 4]. As several Neanderthal genomes of high quality are now available [2, 5, 6], it is possible to identify genetic changes that occurred in many or most Neanderthals, investigate their physiological effects, and assess their consequences when they occur in people today.
Whereas most genetic differences between Neanderthals and modern humans that affect gene products occur singly in genes across the genome, genes that carry several such differences are of particular note. One such case is the gene SCN9A, which encodes the Nav1.7 protein, a voltage-gated sodium channel in which all Neanderthal genomes sequenced to date carry three amino acid substitutions relative to modern humans: M932L; V991L; and D1908G. At these positions, extant monkeys and apes share the modern human residues. Nav1.7 is the only ion channel carrying amino acid substitutions in Neanderthals that is highly expressed in peripheral nerves mediating pain sensation [7]. The channel allows for the passage of sodium ions across the membranes of neurons in response to changes in electrical membrane potential. In humans, loss-of-function mutations of SCN9A cause insensitivity to pain [8] and anosmia [9]. Gain-of-function mutations, on the other hand, are a leading cause of idiopathic small-fiber neuropathy [1], where patients present with sensory symptoms and pain, with pain as the dominant symptom [10].
To investigate the electrophysiological effects of the three substitutions seen in Neanderthals, we synthesized genes encoding the modern human and Neanderthal versions of Nav1.7, transcribed these in vitro, and injected the mRNAs into Xenopus laevis oocytes. We chose this system, rather than, for example, cultured murine dorsal root ganglion cells, in order to test the effects of the three amino acid substitutions when expressed together with relevant human subunits, which differ from those of rodents by 5–47 amino acids. In peripheral nerve endings, Nav1.7 forms complexes with the β3 subunit [11, 12, 13], encoded by SCN3B, which carries no amino acid differences between Neanderthals, Denisovans, and modern humans. When the β3 subunit is expressed together with Nav1.7 in the oocytes, the inactivation curve of the Neanderthal ion channel is shifted by ∼6.1 mV toward less negative values relative to the modern human channel (Figures 1A and 1B ; Table S1; p = 2.9 × 10−5; n = 26 and n = 31, respectively). This results in an increased availability of sodium channels for activation and increased probability that the sodium channel remains open for a longer time once activated and is expected to lower the threshold for the generation of an action potential (see computational model; Figures S1M and S1N).
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Post by Admin on Sept 29, 2023 19:54:10 GMT
 Figure 1 Effects of Neanderthal-Derived Amino Acid Substitutions on Nav1.7 Inactivation (A) Current traces from Xenopus laevis oocytes expressing modern human and Neanderthal (M932L+V991L+D1908G) Nav1.7 proteins together with the auxiliary subunit Navβ3. Following prepulses to three different potentials (shown as examples), currents were elicited by stepping to 0 mV (t = 0). Less negative prepulse potentials resulted in progressively smaller currents due to channel inactivation. This inactivation is more pronounced for the modern human than the Neanderthal protein. (B) Fraction of current as a function of prepulse potential for the modern human and Neanderthal channel proteins. Current amplitudes, measured at t = 10 ms, were normalized to the largest amplitude obtained in each cell. The voltage required for half-maximal inactivation is shifted by +6.1 mV for the Neanderthal protein. (C) Fraction of current as a function of prepulse potential for the modern human and Neanderthal channel proteins when expressed in human embryonic kidney (HEK) cells. Current amplitudes, measured as peak inward current, were normalized to the largest amplitude obtained in each cell. The voltage required for half-maximal inactivation is shifted by +11.7 mV for the Neanderthal protein. (D) Current traces from HEK cells expressing modern human and Neanderthal (M932L+V991L+D1908G) Nav1.7 proteins together with the auxiliary subunit Navβ3 (E) Fraction of current as a function of prepulse potential in Xenopus oocytes for the three single amino acid substitutions individually. (F) Fraction of current in Xenopus oocytes as a function of prepulse potential for Nav1.7 proteins with two substitutions. The voltage required for half-maximal inactivation is shifted by +6.2 mV for the V991L+D1908G protein. Compared to mammalian cells, the steady-state inactivation curves are shifted to the right due to the recording temperature (10°C ± 2°C), the co-expression of the β3 subunit, and the use of Xenopus oocytes, as described [14, 15, 16]. Error bars represent SEM. See also Figures S1 and S2 and Table S1. To examine which of the amino acid substitutions mediates the shift in the inactivation curve, we synthesized and injected mRNAs encoding each of the three amino acid substitutions singly (Figure S2). No single amino acid substitution had any effect on the inactivation of the ion channel (Figure 1E; Table S1). We next investigated the effect of the three possible combinations of two amino acid substitutions. Two of the combinations, M932L+D1908G and M932L+V991L, had no effect on the inactivation. However, V991L+ D1908G caused a shift in the inactivation curve, similar to that of the three substitutions (Figure 1F; Table S1; p = 2.4 × 10−5; n = 24). Thus, an epistatic interaction of the two substitutions V991L and D1908G, which are both located in the intracellular part of the protein, is necessary to elicit the electrophysiological effects. In contrast, M932L, which is located extracellularly, had no detectable effects. We note that the Denisovan genome carries the D1908G substitution in a homozygous form but lacks the other two substitutions. This suggests that the D1908G substitution occurred in the common ancestor of Neanderthals and Denisovans but that it may have had a functional effect only in Neanderthals, where also the V991L substitution occurred. To test whether the effects of the Neanderthal substitutions are also seen in mammalian cells, we transfected human embryonic kidney (HEK) cells with vectors expressing the mRNAs encoding the modern human and the Neanderthal variants of Nav1.7 and the β3 subunit. As in the oocytes, we observe a depolarizing shift in inactivation for the Neanderthal variant of Nav1.7 (Figure 1C; Table S1; p = 9.1 × 10−3; n = 8 and n = 9, respectively). In addition, we observe a depolarizing shift of the activation curve (Figure S1C; Table S1; p = 1.1 × 10−3; n = 8 and n = 9, respectively). When investigated in a simple model of a human peripheral nerve, the depolarizing shift in the inactivation curve has an excitatory effect for suprathreshold stimuli, even in the presence of a depolarizing shift in activation (Figure S1N). Thus, we conclude that the shifts seen in both oocytes and HEK cells are likely to have an excitatory action. We next investigated whether any of the three SCN9A missense mutations (M932L, V991L, and D1908G) exist in present-day humans by examining 2,535 genomes available in the phase III 1000 Genomes (1000G) dataset (Figure 2A). We did not find any of the three variants in the African (N = 507) and European (N = 505) 1000G populations, but M932L and V991L occur in almost perfect linkage disequilibrium (R2 = 0.99) at frequencies of 0.9%–7.8% in Asia and 0.5%–23.8% in the Americas. In addition, D1908G occurs at a frequency of 0%–17.1% in Asia and 0.5%–52.9% in the Americas (Table S2) and tends to be in linkage disequilibrium with M932L+V991L (R2 = 0.26). |
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Post by Admin on Sept 30, 2023 21:02:59 GMT
 Figure 2 Geographical Distribution and Phylogenetic Relationships of SCN9A Variants These variants could have entered the present-day human population from a common ancestor shared with Neanderthals and Denisovans or by introgression from archaic hominins when these met modern humans some 40,000–60,000 years ago. In the latter case, the size of the archaic-like DNA segments on which the variants sit are expected to be substantially larger than if they were inherited from a common ancestor of the three groups, as meiotic recombination will have had less time to reduce their size. To estimate the size of these segments, we identified alleles in this genomic region that are absent in the 1000G Yoruba individuals but occur in homozygous form in the Neanderthal and/or Denisovan genomes and are likely to have entered modern human populations from archaic hominins. We identified one DNA segment (r2 > 0.8) of ∼26 kb around the M932L and V991L substitutions carrying 14 such alleles (chr2:167129256–167155131) and another segment (r2 > 0.8) of ∼110 kb around the D1908G substitution carrying 40 such alleles (chr2:167017315–167126999). Based on the sizes of the two DNA segments and their recombination rates, we concluded that these variants entered the modern human population by introgression from Neanderthals or Denisovans, rather than being inherited from a common ancestor of the groups (p = 0.059 for V991L and M932L; p = 7.8 × 10−16 for D1908G). We estimated the phylogenetic relationships of the two DNA segments overlapping M932L+V991L and D1908G to the corresponding present-day human and Neanderthal DNA segments. For both segments, one group of present-day human DNA sequences is most closely related to the Neanderthal segments (Figures 2B and 2C), and in both instances, these DNA sequences are found in Asia and the Americas. The amino acid substitutions M932L and V991L have previously been associated with increased pain sensitivity and small-fiber neuropathy in experimental and clinical studies in humans [1, 17]. To investigate whether the three introgressed Neanderthal variants affect pain sensitivity in the general human population, we selected 362,944 unrelated individuals of British ancestry in the UK Biobank (UKBB) [18] who had answered questions relating to their experience of pain (Table S3). Although no individual was homozygous for the Neanderthal variants, 1,327 individuals (0.4%) carried all three amino acid substitutions in a heterozygous form. Based on their answers to 19 pain-related questions, these carriers of the three Neanderthal substitutions had experienced one or more forms of pain more often than non-carriers (Figure 3; p = 0.0078; adjusted for age and sex). They also experienced more pain than carriers of only one or two of the Neanderthal substitutions, although these did not differ significantly from individuals carrying none of the Neanderthal substitutions (Figure 3). No individuals with the combination V991L and D1908G were found in the UKBB. Two other substitutions in Nav1.7 that have previously been reported to be associated with increased pain sensitivity are also genotyped in the UKBB and frequent enough to assess their phenotype (W1150R, n = 91,143; R185H, n = 1,369). Neither of these are associated with an increased probability to report pain (p = 0.82 and p = 0.72, respectively), suggesting that their effects are smaller than the Neanderthal-derived variants. |
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