Convergent evolution in human and domesticate adaptation to high-altitude environments | Philosophical Transactions of the Royal Society B: Biological Sciences

Humans and their domestic animals have lived and thrived in high-level environments worldwide for thousands of years. These populations have developed a issue of adaptations to survive in a hypoxic environment, and respective genomic studies have been conducted to identify the genes that drive these adaptations. here, we discuss the versatile adaptations and genetic variants that have been identified as adaptive in human and domestic animal populations and the ways in which convergent evolution has occurred as these populations have adapted to high-level environments. We found that human and domesticate populations have adapted to hypoxic environments in similar ways. specific genes and biological pathways have been involved in high-level adaptation for multiple populations, although the specific variants differ between populations. additionally, we found that the gene EPAS1 is much a aim of selection in hypoxic environments and has been involved in multiple adaptive introgression events. high-level environments exert strong selective pressures, and human and animal populations have evolved in convergent ways to cope with a chronic lack of oxygen .

1. Introduction

Environments shape the genic landscape of the populations that inhabit them. As homo populations have expanded across the populace, they have encountered numerous novel environments, with associated changes in temperature and climate. One of the most challenge environments humans have encountered is high gear altitude. As elevation above ocean degree increases, a decrease in barometric atmospheric pressure results in fewer oxygen molecules in the air, which causes hypoxia. short-run exposure to high-level environments can cause acute altitude sickness, with symptoms including pneumonic and cerebral edema ( fluid collection in the lungs and genius ). long-run exposure to this environment can besides cause pneumonic high blood pressure and is known to increase the risk of pregnancy complications including preeclampsia, which can be fateful [ 1 ]. Organisms that move into high-level environments develop a number of short-run adaptations, including elevated hemoglobin concentration, increased crimson blood cell count and higher resting ventilation. however, populations that have lived in high-level environments over many generations have been subjected to selective pressures and have adapted physiologically and genetically to live in these environments. In many cases, when the populations moved into high-level environments, they brought their domestic animals, including dogs, chickens and livestock. These animals were exposed to the same selective pressures as the human populations, and as a leave, they show like adaptations to hypoxic environments within the same timescales as their human cohabitants. hera, we summarize the history of adaptation to high altitude in homo and domesticate populations worldwide, focusing specifically on convergent adaptations. The term ‘ convergent evolution ‘ can have many definitions, but one definition concerns organisms that are distantly related developing the like or exchangeable familial adaptations that affect the organism ‘s phenotype in the same manner. hera, we focus on two specific cases of convergent development related to high-level adaptation. The inaugural is the direction in which homo or animal populations from different geographic regions have developed similar genic adaptations to living at high gear elevation. The second case is where different species show adaptation in the lapp biological pathways. Three regions of the worldly concern have been studied for populations ‘ adaptation to life at high altitudes : the Andean Altiplano, Qinghai–Tibetan Plateau and the ethiopian Highlands. In many human and animal populations, their physiologic responses to hypobaric hypoxia have been measured, and their genomes have been compared with alike low-level populations in an attack to identify the genetic variants that show signals of positive choice. The genes under choice are often part of the hypoxia-inducible factor ( HIF ) pathway, which governs the body ‘s response to a miss of oxygen. We found that in many cases, the genotypical changes ( either in the like gene or across multiple genes ) differ between populations, but the phenotypical response is the same.

We performed a comprehensive literature search of studies of high-level adaptation in human and domestic animal populations. The majority of these studies focused on genome-wide excerpt scans, although a few studies looked rather at a set list of candidate genes. All genes that were identified by the authors of a study to be meaning and probable crucial for high-level adaptation were included in this analysis. If a study included a functional psychoanalysis, we focused on the genes that were shown to have functional importance related to hypoxia. For Tibetans, which are the most-studied high-level human population, the genes with the strongest signals of choice are accordant across different genomic studies. Andean homo populations, however, show less harmony between studies, as do ethiopian human populations, which are the least-studied high-level human population. We then identified genes that were shared between populations, arsenic well as genes involved in similar pathways. We besides identified gene ontology ( GO ) terms for the biological processes associated with each of the genes ( hypertext transfer protocol : //www.geneontology.org ) using the PANTHER overrepresentation trial ( database and test both released on 10 October 2018 ) and used the PANTHER overrepresentation test to identify molecular affair GO terms for each gene. As alone four populations ( Tibetan humans, Tibetan cattle, Tibetan goats and Andean humans ) had overrepresented GO terms that were statistically meaning with a Bonferroni correction, we used uncorrected p -values to identify GO terms to use for comparison. We then identified common GO terms across populations. A compendious of the populations that have been studied and the genes that have been identified can be found in mesa 1, and a full list of GO terms that are shared between populations can be found in electronic auxiliary material, S1 .

Table 1. A compendious of genes identified as choice targets for high-level adaptation in unlike populations worldwide. Bold genes are shared between populations, and genes in italics contribution GO terms that are common across multiple populations .
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species region genes
human Tibet EPAS1, EGLN1, PPARA, SLC52A3, EDNRA, PTEN, ANGPTL4, Cyp17A1, CYP2E1, HMOX2, CAMK2D, GRB2, ANKH, RP11-384F7.2, HLA-DQB1/HLA-DPB1, ZNF532, KCTD12, VDR, PTGIS, COL4A4, MKL1, HBB,MTHFR
Ethiopia VAV3, RORA, SLC30A9, COL6A1, HGF, BHLHE41, SMURF2, CASP1, CIC, LIPE, PAFAH1B3, CBARA1, ARNT2, THRB, EDNRB
Andes EDNRA, VEGF, TNC, CDH1, PRKAA1, NOS2A, BRINP3, SH2B1, PYGM, TBX5, DST, SGK3, COPS5, ANP32D, SENP1, PRDM1, PFKM, EGLN1
cow Tibet (Yak): ADAM17, ARG2, MMP3, CAMK2B, GCNT3, HSD17B12, WHSC1, Glul (Cattle): EGLN1, HIF3A
Ethiopia BDNF, TFRC, PML
horse Tibet NADH6
Andes EPAS1, TENM2, CYP3A cluster
pig Tibet RGCC, GRIN2B, C9ORF3, GRID1, PLA2G12A, ALB, SPTLC2, GLDC, ECE1, GNG2, PIK3C2G
chicken Tibet SLC35F1, RYR2
dog Tibet EPAS1, HBB, AMOT, SIRT7, PLXNA4, MAFG, ENO3, KIF1C, KIF16B, DNAH9, NR3C2, SLC38A10, ESYT3, RYR3, MSRB3, CDK2, GNB1
goat Tibet EPAS1, SIRT1, ICAM1, YES1, JUP, CDK2, EDNRA, SOCS2, NOXA1, ENPEP, KITLG, FGF5
sheep Tibet FGF7

2. High-altitude adaptations

(a) Tibet

Tibetan populations have possibly been studied the most thoroughly for their adaptations to gamey altitude, based on the act of publications on the capable. At high altitudes ( approx. 3000–4500 meter ), Tibetans have a high rest ventilation but humble arterial oxygen content and low oxygen saturation—of the three populations who have lived at senior high school altitudes for generations, they are the most hypoxic [ 2 ]. There is a correlation in women between higher levels of oxygen saturation and an increase act of surviving children, and alleles undergoing positive selection are associated with more positive pregnancy outcomes in Tibetan women [ 3 ], suggesting that excerpt is distillery acting on this population. Some Tibetans show an increase in hemoglobin assiduity, but alone at altitudes higher than 4000 megabyte [ 2 ]. genetic comparisons of Tibetan and Han Chinese individuals identified EPAS1 ( endothelial PAS world protein 1 ), EGLN1 ( egl-9 family HIF 1 ) and PPARA ( peroxisome proliferator-activated receptor alpha ) [ 4 – 7 ], all of which are part of the HIF nerve pathway. In some of these genes, the genetic mutation that may cause the physiologic response has been identified [ 8 ]. For case, EGLN1 is involved in HIF degradation, which triggers crimson blood cell production. A missense mutation in EGLN1 results in a miss of lift hemoglobin, at least under high-level conditions [ 9 ]. The EPAS1 allele found in Tibetans was found to be associated with hemoglobin concentration as well [ 10 ]. The EPAS1 variant in Tibetans shows the most differentiation from the Han Chinese [ 11 ] and shows more differentiation than that of any genetic variant between any two similarly close related populations [ 12 ]. amazingly, the EPAS1 haplotype found in Tibetans is alone shared with a small total of Han Chinese and the Denisovan genome, which suggests that the Denisovan allele has a function in high-level adaptation in Tibetans. This is an exercise of adaptive introgression, in which gene hang between species or subspecies results in the introduction of a genetic version that increases seaworthiness [ 13 – 15 ]. A 3.4 kilobit deletion near EPAS1 is found at high frequencies in Tibetans and is in potent linkage disequilibrium with the EPAS1 haplotype, but it is extremely rare global and may be a functional contributor to hypoxic permissiveness in Tibetans [ 16 ]. A more recent sketch sequencing solid genomes identified a much larger haplotype block surrounding EPAS1, a well as extra candidate genes [ 17 ]. An elaborate study of populations across the Himalayan area, including five ancient Himalayan genomes, suggests that most himalayan populations derive a large proportion of their ancestry from a single ancestral population who adapted to high altitude [ 18 ]. however, mix with other nearby populations has been detected [ 19 – 22 ], suggesting a building complex demographic history of the area. multiple gene variants that show signals of choice in advanced Tibetans, including EPAS1, EGLN1 and SLC52A3 ( solute carrier wave family 52 member 3 ), were besides found in the ancient Nepalese genomes, which range in historic period from 1200 to 3100 years before present [ 18, 23 ]. however, only some variants of these genes found in modern populations were found in the ancient genomes ( for case, 6 of 26 in EPAS1 and 11 of 21 in EGLN1 ), suggesting that choice for some of these gene variants has occurred recently. Humans are not the lone species that has adapted to this environmental recess in Tibet. The Tibetan Mastiff is a chase breed that was developed to live at high altitudes, and they show a lowered hemoglobin concentration compared with lowland Chinese native dogs [ 24 ]. A choice scan identified the target genes EPAS1 and HBB ( hemoglobin fractional monetary unit beta ), both of which have besides been implicated in high-level adaptation in Tibetan human populations. Out of 16 genes that showed signals of positive choice, 12 were linked with hypoxia. further exploration of EPAS1 in Tibetan mastiffs showed four novel non-synonymous mutations in the gene, all of which are associated with decreased blood flow underground [ 25 ]. A more holocene study has suggested that the EPAS1 version in Tibetan Mastiffs is actually the result of adaptive introgression with Tibetan wolves [ 26 ]. An extra analysis focusing on the X chromosome identified the gene AMOT ( angiomotin ) as a target of choice, which is involved in blood pressure regulation [ 27 ]. In accession to dogs, numerous other domesticated animals living on the Tibetan Plateau show similar adaptations to the homo populations. For case, there are multiple farrow populations living at high elevation in Tibet, all of which show signals of excerpt for variants of hypoxia-related genes [ 28 ]. Some genotypical changes, such as variants of RGCC ( governor of cell bicycle ) are shared between populations, while others, such as a GRIN2B discrepancy ( glutamate ionotropic receptor NMDA type fractional monetary unit 2B ) are singular to specific populations, demonstrating a combination of convergent development and novel variation to cope with the challenging environment of eminent altitudes. Tibetan chickens have an increased crimson blood cell count and blood oxygen affinity relative to early chicken populations [ 29 ], similar to Andean human populations, and a excerpt scan identified genes that had been positively selected and are involved in the calcium-signalling nerve pathway, including RYR2 ( ryanodine receptor 2 ), which may be linked to high-level tolerance [ 30 ]. The Tibetan cashmere capricorn shows signals of choice in a number of genes that may be associated with hypoxia, including EPAS1 [ 31 ]. other breeds of goat be on the Tibetan Plateau show signals of positive selection in other genes, including CDK2 ( cyclin-dependent kinase 2 ) and EDNRA ( endothelin sense organ type A ) [ 32 ]. Tibetan sheep breeds living at high altitude plowshare a highly conserved functional variant in the showman region of FGF7 ( keratinocyte emergence agent 7 ), a gene that is involved in pneumonic diseases, suggesting that recording transition of the gene helps with survival in a hypoxic environment [ 33 ]. A study of Tibetan knight mitochondrial genomes identified multiple non-synonymous substitutions in the NADH6 ( ubiquinone oxidoreductase kernel fractional monetary unit 6 ) gene, suggesting an affair of energy metabolism in their adaptation to hypoxic conditions [ 34 ]. A comparison of the alpine yak genome to the overawe genome showed increase deviation in gene families responsible for hypoxic stress, and hypoxia-associated genes like ADAM17 ( ADAM metallopeptidase domain 17 ) and ARG2 ( arginase 2 ) show signals of positive excerpt [ 35 ]. A more late study of Tibetan cattle identified an association between an EGLN1 variant and lowered hemoglobin concentration, and the adaptive form was likely introgressed from hybridization with yaks [ 36 ] .

(b) Andes

The first population to be studied for their adaptation to high gear altitude was the Andeans, who live at 2500–4500 m. While Andeans thrive at eminent altitudes comparable to those that Tibetans experience, they have adapted to the hypoxic environment in unlike ways [ 37 ]. Compared with low-lying populations, they show a normal rest breathing, but a slightly decreased oxygen saturation, increased hemoglobin concentration and a higher arterial oxygen subject [ 2 ]. This is in contrast to Tibetan populations, who show no elevation in hemoglobin except at altitudes above 4000 m. A campaigner gene study comparing Andean native american populations to lowland native american populations identified signals of positive excerpt for a count of genes, including EDNRA, PRKAA1 ( protein kinase, AMP-activated and alpha 1 catalytic fractional monetary unit ) and NOS2A ( azotic oxide synthase 2A ) [ 38 ]. In a follow-up genome-wide report, EGLN1 ( egl-9 family HIF 1 ) was besides identified when entirely considering the genes in the HIF nerve pathway [ 7 ]. Another genome-wide report of Andean high-level populations identified multiple genes under choice that are associated with cardiovascular function, including BRINP3 ( BMP/retinoic acid-inducible neural particular 3 ) [ 39 ]. This suggests that alternatively of choice targeting genes associated with the HIF nerve pathway, as is the subject with Tibetans, excerpt in Andeans alternatively has focused on modifications of the cardiovascular system to cope with high altitudes. reproducible with this hypothesis, a analyze of ancient Andean genomes dating to equally early as 7000 years before salute uncover choice in DST ( dystonin ), a gene involved in cardiovascular routine [ 40 ]. multiple studies comparing high-level individuals with and without chronic mountain nausea far identified extra genes that seem to protect against chronic disease at high altitude, including ANP32D ( acidic nuclear phosphoprotein 32 family penis D ), SENP1 ( SUMO-specific protease 1 ) and PRDM1 ( PR/SET domain 1 ) [ 41, 42 ]. domestic animals from the Andes have besides been studied for their adaptation to high altitudes. Llamas, equally well as their close relatives the alpaca and vicuña, were adapted to high altitudes before they were domesticated and have a lower red rake cell count and hemoglobin levels relative to Andean humans at eminent altitude. however, it has been suggested that the smaller size and singular shape of camelid loss blood cells better facilitate oxygen impregnation [ 43 ]. additionally, llama hemoglobin has a high oxygen affinity, such that oxygen saturation stays above 90 % both at sea horizontal surface and at eminent altitude [ 44 ]. similarly, guinea pigs, which were besides hypoxia-adapted anterior to tameness, show a identical limited increase in crimson blood cellular telephone count at higher altitudes and merely a flimsy decrease in oxygen impregnation at gamey altitudes compared with low-lying populations [ 45 ]. even Andean wimp populations, which were introduced to the region following european contact ( i.e. less than 500 years before give ) have haemoglobin with a higher oxygen affinity, suggesting that adaptation to high elevation can occur within a population even in a relatively light period of time [ 46 ]. investigation of the genic changes underlying the physiologic changes in Andean domesticates has been limited to studies of two species : alpaca and horses. Alpacas and other camelids parcel an ancient helix-loop-helix omission from the HIF-1A protein with cetaceans and even-toed ungulate, which may contribute to their reduced hypoxic reply [ 47 ]. A genomic study of feral peruvian horses, which are descended from the horses the spanish conquistadors introduced and nowadays thrive at high altitudes, identified numerous genes showing signals of survival, including several associated with nervous system growth american samoa well as EPAS1 [ 48 ] .

(c) Ethiopia

ethiopian populations are the least study for their adaptations to high elevation and are besides more difficult to study. ethiopian highlanders are not an isolated population like Tibetans and besides show testify of gene flow from outside of Africa [ 49 ], which can make it more difficult to identify adaptive variants. Unlike the Andeans and Tibetans, Ethiopians show no physiological response to high altitudes [ 2 ]. Their respiration, oxygen impregnation and hemoglobin concentration are all exchangeable to the values of humans at sea level. however, one cogitation found that high-level ethiopian populations exhibit higher hemoglobin levels at high altitude ( compared with moo altitude ) and besides identified differences in hemoglobin levels between closely related high-level ethiopian populations living at the lapp altitude [ 49 ]. The effects of hypoxia may be lessened in these high-level populations, given that they live at a slightly lower elevation compared with Tibetans and Andeans ( 2500–3500 molarity ). however, lowland populations living at high altitude would be expected to show elevated hemoglobin levels and increase respiration, demonstrating that ethiopian highlanders do show some adaptation to high-level environments. A campaigner gene cogitation in Ethiopians identified multiple genes associated with the HIF nerve pathway, including VAV3 ( vav guanine nucleotide exchange factor 3 ), all of which are discrete from those identified in Andeans and Tibetans [ 50 ]. A comparison between two populations, the Amhara who have lived at high altitudes for thousands of years and the Oromo who only moved into high-level environments in the past 500 years, identified excerpt on hypoxia-associated genes including RORA ( RAR-related orphan receptor A ) in the Amhara but no genes were identified in the Oromo, suggesting that they had not lived at high altitudes long adequate to show signs of adaptation [ 51 ]. A more late study of the Amhara and Oromo that made corrections to account for non-African admixture identified BHLHE41 ( basic helix-loop-helix class member E41 ), which is involved in the knowledgeability of the hypoxic reply via the HIF pathway, as the gene with the strongest choice signal in both populations [ 52 ]. This sketch besides suggested that the Oromo may have acquired the adaptive BHLHE41 form through mix with the Amhara, allowing them to adapt to high altitudes more quickly. An extra three genes, CIC ( capicua transcriptional repressor ), LIPE ( lipase E, hormone-sensitive type ) and PAFAH1B3 ( platelet-activating gene acetylhydrolase 1b catalytic fractional monetary unit 2 ), were identified using whole-genome sequence with a subsequent demonstration of increase hypoxia tolerance in the orthologous genes in Drosophila [ 53 ]. A fourth gene, EDNRB ( endothelin receptor type B ), was shown to show increase hypoxia allowance when knocked down in mouse [ 54 ]. High-altitude cattle breeds living in Ethiopia show no exalted hemoglobin levels or red blood cell counts and a lower oxygen saturation relative to other cattle breeds living at senior high school altitudes in the area [ 55 ], a exchangeable adaptation to ethiopian human populations [ 2 ]. Although oxygen saturation levels below 80 % were reported as deadly for lowland cattle breeds in early studies, the high-level ethiopian cattle breeds were thriving with a much lower oxygen saturation level of 68 % [ 55 ]. A comparison of high-level and low-level ethiopian cattle breeds showed senior high school familial differentiation between the populations for multiple genes associated with hypoxia, including BDNF ( brain-derived neurotrophic factor ), TFRC ( transferrin receptor ) and PML ( promyelocytic leukemia ), suggesting that these genes have been selected for increased hypoxia allowance [ 56 ] .

3. Discussion

(a) Convergent evolution at the gene level

Although there is a considerable variation in how different human and animal populations have responded to high-level environments, there are several examples of convergent evolution across populations. A map of all populations studied and the convergent evolutionary connections between them is summarized in figure 1. For exercise, HBB shows the signals of positive choice both in human and in frump populations, and EGLN1 was identified as adaptive in Tibetan and Andean human populations and in Tibetan homo and cattle populations. EDNRA variants are besides selected for in two human populations ( Andeans and Tibetans ) adenine well as in Tibetan goats. EDNRB, a close relate gene, was implicated in hypoxia allowance in ethiopian humans adenine well. additionally, convergent development seems to have occurred in different genes involved in the like pathways in different populations. For exemplar, FGF5 in cashmere goats and FGF7 in Tibetan sheep are both fibroblast growth factors, which can help protect against lung injury. PML in ethiopian cattle, PTEN ( phosphatase and tensin homolog ) in Tibetan humans and CDK2 in Tibetan goats are all involved with triggering apoptosis, which is a common response of cells exposed to hypoxic environments, either owing to hypoxic stress or owing to the accumulation of deleterious mutations as a result of hypoxia [ 57 ]. PRKAA1 and LIPE in ethiopian humans and PPARA in Tibetan humans are both associated with lipid metamorphosis, which can be negatively impacted by chronic hypoxia as it increases the risk of developing fatso liver disease [ 58 ]. additionally, RYR3 in Tibetan mastiffs, RYR2 in Tibetan chickens and GRIN2B in Tibetan pigs are all associated with the regulation of calcium channels, which are authoritative for a number of biological functions, including vasoconstriction [ 59 ]. Figure 1.

Figure 1. A map summarizing the genomic studies done on human and domesticate populations at high altitude, highlighting the convergent evolution between populations. The three high-altitude regions are highlighted, and the human and animal icons show the different species that have been studied in each region. Lines connecting populations indicate adaptation in the same or similar genes—solid lines indicate adaptation in the same gene, with EPAS1 highlighted in red, and dashed lines indicate similar genes that show adaptation across multiple populations. Pig and sheep icons from icons8.com, cow icon by Olivier Guin from thenounproject.com, chicken icon and goat icon by tan from onlinewebfonts.com and human icon by Dave Gandy from fontawesome.io, used under Creative Commons.

EPAS1 has been shown to be under incontrovertible survival in Tibetan humans, the Tibetan mastiff, feral Andean horses and kashmir capricorn populations living on the Tibetan Plateau. Interestingly, EPAS1 is besides one of the few genes that has been identified to be introduced through adaptive introgression, possibly from Denisovans into humans [ 12 ] and from Tibetan wolves to the Tibetan Mastiff [ 26 ]. In another exemplify of adaptive introgression, an EGLN1 variant that is adaptive to high-level environments was likely introduced into Tibetan cattle populations through interbreeding with yaks [ 36 ]. adaptive introgression is amazingly a common component of high-level adaptation, probably because admixture with another species that is already adapted to an environmental niche is generally a more effective way of acquiring adaptive variants than random, de novo mutation. Although not specifically an exercise of adaptive introgression, gene flow from the ethiopian Amhara population probably introduced an adaptive BHLHE41 form to the Oromo, who migrated much more recently to gamey altitudes. This is specially true in cases such as that of the Tibetan Mastiff, where the adaptive EPAS1 variant was not already segregating in the lowland population [ 26 ]. By interbreeding with the Tibetan beast [ 60 ], which had lived at high altitudes for thousands of years prior to the arrival of the domestic dogs, Tibetan Mastiffs likely promptly acquired the familial variants needed to thrive on the Tibetan Plateau. EPAS1 variants have besides been identified as adaptive in numerous other animal species, including the Tibetan wolf [ 60 ], a Tibetan hot-spring snake [ 61 ], a rodent known as the tableland zokor [ 62 ], the High Himalayan frog [ 63 ] and the snow leopard [ 64 ]. It is surprise that despite a big number of genes implicated in high-level adaptation, EPAS1 variants are involved thus frequently. however, other examples of parallel development across distantly related taxa have been identified, and it has been suggested that there are genic ‘ hotspots ’, where some genes are more likely to be modified in response to selective blackmail than others [ 65, 66 ]. Genes may be more likely to evolve if they have a larger effect size, a higher mutant rate, or a higher likelihood of mutations being beneficial [ 66 ]. It is possible that some characteristics of the EPAS1 gene make it more probable to change in reception to selective pressures or to be spread to early species through introgression.

(b) Convergent evolution at the pathway level

At the level of biological function, many high-level populations parcel similar GO terms ( human body 2 ; electronic supplementary material, S1 ). here, we focus on terms that were shared across the majority of populations. Nine of the populations ( Tibetan chickens, cattle, dogs, humans and yaks ; Andean horses and humans and ethiopian cattle and humans ) shared three GO terms, wholly related to the hypoxia response : reception to decreased oxygen levels, answer to oxygen levels and reaction to hypoxia. other GO terms that were overrepresented in at least half of the human and domesticate populations are related to development ( anatomical reference structure morphogenesis, system development, multicellular organism development, muscle social organization development, blood vessel morphogenesis and regulation of biological quality ), responses to chemicals ( reply to chemical and cellular response to chemical stimulation ) and stress ( reaction to stress and response to oxidative try ), a well as regulation of arrangement ( regulation of recording by RNA polymerase II ) and nucleic acid production ( positive regulation of nucleobase-containing compound metabolic march ). These coarse GO terms suggest that while modifications to the reply to hypoxia and other stressors are crucial for increased seaworthiness in high-level populations, other pathways are besides involved in helping improve fitness in these populations, including developmental changes ( including changes to blood vessels and muscles ), transition of transcription and the responses of cells to stimuli. Interestingly, these GO terms are found across all three regions studied, emphasizing that convergent phenotypical changes occur in disparate populations as they adapt to high elevation, even if the specific genes that are selected for are different. A tilt of the genes identified in each population with the above GO terms can be found in electronic supplementary corporeal, S2. Figure 2.

Figure 2. A summary of the GO terms shared between high-altitude populations. (a) The pairwise counts of all GO terms shared between populations. (b) The pairwise counts of common GO terms (found in at least half of the high-altitude populations sampled) shared between populations. Tibetan Horses are omitted from (b) because they did not have any of the common GO terms. (Online version in colour.)

(c) Phenotypic but not genotypic convergence

In many cases, when the lapp gene is selected for across multiple populations, we found that different single nucleotide polymorphism ( SNPs ) have been implicated as adaptive in different populations. therefore, while we see convergence in the genes under excerpt, the specific variants differ. This implies some redundancy in these genes, where multiple mutations can have the lapp effect. Several of the changes identified across populations in the HIF pathway consequence in decreased gene affair or activity, and this decrease in affair can likely be caused by a total of unique mutations. This phenomenon has besides been identified in other cases of homo adaptation. For example, the 32-base pair deletion in CCR5 that promotes HIV1 immunity is found primarily in individuals of european descent [ 67 ], but other variants with a alike function have been identified in african populations [ 68 ]. additionally, lactase perseverance has arisen independently in multiple populations, with different adaptive variants arising in unlike regions of the universe [ 69 ]. This suggests that this type of convergence, where different variants of the like gene have the same phenotypical effect, is a reasonably common happening. Although many of the same genes and pathways show alike signals of choice across species, the nature of the SNPs under choice seems to differ between humans and other species. In humans, closely all of the adaptive mutations that have been identified seem to be outside of gene coding regions, but in domesticated species, there are multiple examples of non-synonymous mutations under choice. These include multiple genes ( EPAS1, HBB and AMOT ) in the Tibetan Mastiff [ 25 – 27 ], arsenic well as EPAS1 in cashmere goats [ 31 ], NADH6 in Tibetan horses [ 34 ] and the modified HIF1A protein in alpaca and other camelids [ 47 ]. In other cases, however, including FGF7 in Tibetan sheep [ 33 ] and RYR2 in Tibetan chickens [ 30 ], regulative regions have alternatively been a selection target. Generally, mutations in cis -regulatory regions are more likely to be selected for than mutations in coding regions, as they are less likely to have pleiotropic effects, which could be deleterious [ 70 ]. It is consequently unexpected that non-synonymous mutations selected in high-level populations are reasonably common in domesticate species. however, the tameness process and ongoing animal farming exert potent selective pressures on domesticates, and the persuasiveness of choice can overcome the possible negative effects of selecting for mutations in the cryptography area [ 71 ] .

(d) Limitations of current studies

One caveat to this meta-analysis is that it can be unmanageable to identify specifically convergent genetic changes in these genes. The majority of these studies have focused on identifying regions that differ between related lowland and upland populations, quite than trying to identify functional changes and the effect they would have on an organism ‘s phenotype. While some coding-region changes have been identified in Tibetan humans [ 9, 16 ] and goats [ 31 ] and Andean humans [ 41 ], the majority of SNPs have been identified in non-coding regions, suggesting that gene regulation is affected. additionally, few studies have attempted to identify genome-wide associations between genotype and phenotype [ 3, 10 ] and only a handful of physiologic studies have been conducted in domesticated populations, making it challenging to show convergence in genetic changes and their effects across species. It is besides potential that selection is not acting on the physiological traits being measured ( e.g. hemoglobin assiduity and oxygen saturation ), but these phenotypic changes are alternatively a resultant role of excerpt for a different trait. however, we have identified convergent physiological changes between species, including increased oxygen affinity in Tibetan and Andean chickens and Andean humans and decreased hemoglobin concentration in Tibetan humans and dogs. To better identify the cases of convergent development and to determine if these campaigner genes are actually being modified in twin directions across populations, farther exploration of the physiologic and functional changes in high-level populations is needed to identify and characterize how genic variants are driving this adaptation to high elevation. additionally, there is a diagonal in identifying genes that are part of the HIF pathway, which may be over-inflating the importance of hypoxia-associated genes for adaptation to high altitudes. Some studies have specifically examined hypoxia-associated genes only [ 38, 56 ], while others identify a issue of candidate genes but lone focus on those related to hypoxia, despite the fact that other biological processes are authoritative in high-level adaptation, as shown by the GO psychoanalysis. While adaptation to the reduced-oxygen environment seems to be significant for the majority of high-level populations, an adaptation of the cardiovascular system to handle the increased affection rate and crimson blood cell count and changes to the placenta and other biological processes involved in pregnancy are besides significant to ensure that the population thrives at higher elevations. extra adaptations would besides be needed to cope with the cold temperatures and increased UV radiotherapy at higher altitudes .

(e) Future directions

Although many domesticates have been studied for their adaptations to high altitude, the majority of genetic studies have focused on Tibetan human and animal populations. More extensive genic and phenotypical studies of ethiopian human populations are needed to help further clarify the ways in which unlike populations adapt to higher altitudes. With a broad understand of the genic variants that have been selected for in Tibetans, Andeans and Ethiopians, it will be potential to compare adaptations between populations who have lived at high altitudes for retentive periods of clock time ( Tibetans and some Ethiopians ) to those who have moved into high-level environments more recently ( such as the Andeans ). Cattle, chickens and early domesticates have besides lived on the Andean Plateau and in the ethiopian Highlands, and by studying the genes under choice in those populations, we gain a better understand of how domesticates adapt to newly environments, and whether these adaptations show phenotypical or genotypical overlap. Guinea pigs and camelids lived at high altitudes retentive earlier humans domesticated them, and it would be interesting to compare the adaptations of these species to those of species that were domesticated before they were exposed to hypoxic conditions, such as andean chickens. physiologic analyses of domestic species should besides be expanded, to allow for more steer comparisons between populations and to identify links between genotype and phenotype. last, while some ancient DNA studies of high-level populations have been conducted [ 18, 40 ], farther survey of ancient human and animal populations at eminent altitude can reveal how these populations adapted to high altitudes over prison term. By continuing to study the populations that live and thrive at high altitudes, we gain a better understand of the convergent ways in which species adapt to new environments. The study of homo and domesticate populations in Tibet, the Andes and Ethiopia has enabled us to begin to understand how species adapt to life at senior high school altitude and has besides provided insight about the nature of convergent development. high gear altitude is an excellent natural experiment for studying convergent development because it has an ecological context, and hypoxia affects all species living at high altitudes. These regions have been populated with many different species, including barbarian animals, domesticates and humans, and in some cases ( such as in humans and in cattle ), we have parallel examples of the like species immigrating to high-level environments in different regions of the worldly concern. This enables us to capture the width of adaptation to a single environment. We have found that in some cases, convergent evolution occurs in particular genes ( such as EPAS1 ), although the specific variants involved in adaptation may differ across populations. additionally, although some pathways ( such as the hypoxia reply ) seem to be more normally involved in adaptation to a common environment, different populations follow different routes to become adapted to their environment. We found that in many cases, the phenotypical consequence and seaworthiness result are the same despite genotypical differences, suggesting that convergent evolution can occur in a multitude of ways. With profoundly familial and phenotypical studies of modern and ancient high-level populations, adenine well as a functional assessment of the putatively selected variants, we can more fully characterize the nature of familial convergence as populations worldwide have adapted to liveliness at high elevation .

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Authors’ contributions

K.E.W. participated in the design of the study, conducted the research and drafted the manuscript. E.H.-S. conceived of the report, designed the study and helped draft the manuscript. Both authors gave concluding blessing for publication .

Competing interests

We have no competing interests .

Funding

K.E.W. and E.H.-S. were funded by NSF award grant no. 1557151 and NIH award grant no. 1R35GM128946-01 .

Footnotes

One contribution of 16 to a theme issue ‘Convergent evolution in the genomics era: new insights and directions’.

Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.4468721.

© 2019 The Authors. Published by the Royal Society under the terms of the creative Commons Attribution License hypertext transfer protocol : //creativecommons.org/licenses/by/4.0/, which permits unrestricted practice, provided the original writer and source are credited .

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