scholarly journals Adaptive landscape of protein variation in human exomes

2018 ◽  
Author(s):  
Ravi Patel ◽  
Maxwell D. Sanderford ◽  
Tamera R. Lanham ◽  
Koichiro Tamura ◽  
Alexander Platt ◽  
...  
Keyword(s):  
Neutral Evolution ◽  
Adaptive Landscape ◽  
Human Populations ◽  
Missense Mutations ◽  
Adaptive Variation ◽  
Selective Pressures ◽  
Allele Frequency Data ◽  
Adaptive Mechanisms ◽  
Association Data ◽  
Reversal Of Fortune

AbstractThe human genome contains hundreds of thousands of missense mutations. However, only a handful of these variants are known to be adaptive, which implies that adaptation through protein sequence change is an extremely rare phenomenon in human evolution. Alternatively, existing methods may lack the power to pinpoint adaptive variation. We have developed and applied an Evolutionary Probability Approach (EPA) to discover candidate adaptive polymorphisms (CAPs) through the discordance between allelic evolutionary probabilities and their observed frequencies in human populations. EPA reveals thousands of missense CAPs, which suggest that a large number of previously optimal alleles had experienced a reversal of fortune in the human lineage. We explored non-adaptive mechanisms to explain CAPs, including the effects of demography, mutation rate variability, and negative and positive selective pressures in modern humans. Our analyses suggest that a large proportion of CAP alleles have increased in frequency due to beneficial selection. This conclusion is supported by the facts that a vast majority of adaptive missense variants discovered previously in humans are CAPs, and that hundreds of CAP alleles are protective in genotype-phenotype association data. Our integrated phylogenomic and population genetic EPA approach predicts the existence of thousands of signatures of non-neutral evolution in the human proteome. We expect this collection to be enriched in beneficial variation. EPA approach can be applied to discover candidate adaptive variation in any protein, population, or species for which allele frequency data and reliable multispecies alignments are available.

scholarly journals FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes

2017 ◽  
Vol 115 (2) ◽  
pp. E253-E262 ◽  
Author(s):  
Ho-Keun Kwon ◽  
Hui-Min Chen ◽  
Diane Mathis ◽  
Christophe Benoist
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Central Element ◽  
Active Regions ◽  
Immunological Tolerance ◽  
Human Populations ◽  
Missense Mutations ◽  
Normal Numbers ◽  
Transcriptional Targets

FoxP3+ regulatory T cells (Tregs) are a central element of immunological tolerance. FoxP3 is the key determining transcription factor of the Treg lineage, interacting with numerous cofactors and transcriptional targets to determine the many facets of Treg function. Its absence leads to devastating lymphoproliferation and autoimmunity in scurfy mutant mice and immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) patients. To finely map transcriptionally active regions of the protein, with respect to disease-causing variation, we performed a systematic alanine-scan mutagenesis of FoxP3, assessing mutational impacts on DNA binding and transcriptional activation or repression. The mutations affected transcriptional activation and repression in a variegated manner involving multiple regions of the protein and varying between different transcriptional targets of FoxP3. There appeared to be different modalities for target genes related to classic immunosuppressive function vs. those related to atypical or tissue-Treg functions. Relevance to in vivo Treg biology was established by introducing some of the subtle Foxp3 mutations into the mouse germline by CRISPR-based genome editing. The resulting mice showed Treg populations in normal numbers and exhibited no overt autoimmune manifestations. However, Treg functional defects were revealed upon competition or by system stress, manifest as a strikingly heightened susceptibility to provoked colitis, and conversely by greater resistance to tumors. These observations suggest that some of the missense mutations that segregate in human populations, but do not induce IPEX manifestations, may have unappreciated consequences in other diseases.

scholarly journals Human influences on antipredator behaviour in Darwin’s finches

2019 ◽  
Author(s):  
Kiyoko M. Gotanda
Keyword(s):  
Urban Areas ◽  
Antipredator Behaviour ◽  
Human Populations ◽  
Urban Populations ◽  
Darwin's Finches ◽  
Selective Pressures ◽  
Invasive Predators ◽  
Darwin’S Finches ◽  
History Of ◽  
Predator Eradication

Abstract1) Humans exert dramatic influences upon the environment, creating novel selective pressures to which organisms must adapt. On the Galapagos, humans have established a permanent presence and have altered selective pressures through influences such as invasive predators and urbanization, affecting iconic species such as Darwin’s finches.2) Here, I ask two key questions: (i) does antipredator behaviour (e.g. FID) change depending on whether invasive predators are historically absent, present, or eradicated? and (ii) to what degree does urbanization affect antipredator behaviour? This study is one of the first to quantify antipredator behaviour in endemic species after the eradication of invasive predators. This will help to understand the consequences of invasive predator eradication and inform conservation measures.3) I quantified flight initiation distance (FID), an antipredator behaviour, in Darwin’s finches, across multiple islands in the Galapagos that varied in the presence, absence, or successful eradication of invasive predators. On islands with human populations, I quantified FID in urban and non-urban populations of finches.4) FID was higher on islands with invasive predators compared to islands with no predators. On islands from which invasive predators were eradicated ∼11 years previously, FID was also higher than on islands with no invasive predators. Within islands that had both urban and non-urban populations of finches, FID was lower in urban finch populations, but only above a threshold human population size. FID in larger urban areas on islands with invasive predators was similar to or lower than FID on islands with no history of invasive predators.5) Overall, these results suggest that invasive predators can have a lasting effect on antipredator behaviour, even after eradication. Furthermore, the effect of urbanization can strongly oppose the effect of invasive predators, reducing antipredator behaviour to levels lower than found on pristine islands with no human influences. These results improve our understanding of human influences on antipredator behaviour which can help inform future conservation and management efforts on islands.

scholarly journals Neutral evolution test of the spike protein of SARS-CoV-2 and its implications in the binding to ACE2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Georgina I. López-Cortés ◽  
Miryam Palacios-Pérez ◽  
Gabriel S. Zamudio ◽  
Hannya F. Veledíaz ◽  
Enrique Ortega ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Neutral Theory ◽  
Purifying Selection ◽  
Spike Protein ◽  
Health Concern ◽  
Neutral Evolution ◽  
Evolutionary Mechanisms ◽  
Theory Of Evolution ◽  
Selective Pressures

AbstractAs the SARS-CoV-2 has spread and the pandemic has dragged on, the virus continued to evolve rapidly resulting in the emergence of new highly transmissible variants that can be of public health concern. The evolutionary mechanisms that drove this rapid diversity are not well understood but neutral evolution should open the first insight. The neutral theory of evolution states that most mutations in the nucleic acid sequences are random and they can be fixed or disappear by purifying selection. Herein, we performed a neutrality test to better understand the selective pressures exerted over SARS-CoV-2 spike protein from homologue proteins of Betacoronavirus, as well as to the spikes from human clinical isolates of the virus. Specifically, Tyr and Asn have higher occurrence rates on the Receptor Binding Domain (RBD) and in the overall sequence of spike proteins of Betacoronavirus, whereas His and Arg have lower occurrence rates. The in vivo evolutionary phenomenon of SARS-CoV-2 shows that Glu, Lys, Phe, and Val have the highest probability of occurrence in the emergent viral particles. Amino acids that have higher occurrence than the expected by the neutral control, are favorable and are fixed in the sequence while the ones that have lower occurrence than expected, influence the stability and/or functionality of the protein. Our results show that most unique mutations either for SARS-CoV-2 or its variants of health concern are under selective pressures, which could be related either to the evasion of the immune system, increasing the virus’ fitness or altering protein – protein interactions with host proteins. We explored the consequences of those selected mutations in the structure and protein – protein interaction with the receptor. Altogether all these forces have shaped the spike protein and the continually evolving variants.

scholarly journals Nonparametric coalescent inference of mutation spectrum history and demography

2021 ◽  
Vol 118 (21) ◽  
pp. e2013798118
Author(s):  
William S. DeWitt ◽  
Kameron Decker Harris ◽  
Aaron P. Ragsdale ◽  
Kelley Harris
Keyword(s):  
Evolutionary History ◽  
Genomic Variation ◽  
Mutation Spectrum ◽  
Human Populations ◽  
Effective Population ◽  
Allele Frequency Data ◽  
Constant Rate ◽  
Boom And Bust ◽  
Genomic Regions ◽  
Mutational Processes

As populations boom and bust, the accumulation of genetic diversity is modulated, encoding histories of living populations in present-day variation. Many methods exist to decode these histories, and all must make strong model assumptions. It is typical to assume that mutations accumulate uniformly across the genome at a constant rate that does not vary between closely related populations. However, recent work shows that mutational processes in human and great ape populations vary across genomic regions and evolve over time. This perturbs the mutation spectrum (relative mutation rates in different local nucleotide contexts). Here, we develop theoretical tools in the framework of Kingman’s coalescent to accommodate mutation spectrum dynamics. We present mutation spectrum history inference (mushi), a method to perform nonparametric inference of demographic and mutation spectrum histories from allele frequency data. We use mushi to reconstruct trajectories of effective population size and mutation spectrum divergence between human populations, identify mutation signatures and their dynamics in different human populations, and calibrate the timing of a previously reported mutational pulse in the ancestors of Europeans. We show that mutation spectrum histories can be placed in a well-studied theoretical setting and rigorously inferred from genomic variation data, like other features of evolutionary history.

scholarly journals Genomic evidence for shared common ancestry of East African hunting-gathering populations and insights into local adaptation

2019 ◽  
Vol 116 (10) ◽  
pp. 4166-4175 ◽  
Author(s):  
Laura B. Scheinfeldt ◽  
Sameer Soi ◽  
Charla Lambert ◽  
Wen-Ya Ko ◽  
Aoua Coulibaly ◽  
...  
Keyword(s):  
Adaptive Landscape ◽  
African History ◽  
Common Ancestry ◽  
East African ◽  
Selective Pressures ◽  
Genome Wide ◽  
A Genome ◽  
African Populations ◽  
Anatomically Modern Humans ◽  
Show Evidence

Anatomically modern humans arose in Africa ∼300,000 years ago, but the demographic and adaptive histories of African populations are not well-characterized. Here, we have generated a genome-wide dataset from 840 Africans, residing in western, eastern, southern, and northern Africa, belonging to 50 ethnicities, and speaking languages belonging to four language families. In addition to agriculturalists and pastoralists, our study includes 16 populations that practice, or until recently have practiced, a hunting-gathering (HG) lifestyle. We observe that genetic structure in Africa is broadly correlated not only with geography, but to a lesser extent, with linguistic affiliation and subsistence strategy. Four East African HG (EHG) populations that are geographically distant from each other show evidence of common ancestry: the Hadza and Sandawe in Tanzania, who speak languages with clicks classified as Khoisan; the Dahalo in Kenya, whose language has remnant clicks; and the Sabue in Ethiopia, who speak an unclassified language. Additionally, we observed common ancestry between central African rainforest HGs and southern African San, the latter of whom speak languages with clicks classified as Khoisan. With the exception of the EHG, central African rainforest HGs, and San, other HG groups in Africa appear genetically similar to neighboring agriculturalist or pastoralist populations. We additionally demonstrate that infectious disease, immune response, and diet have played important roles in the adaptive landscape of African history. However, while the broad biological processes involved in recent human adaptation in Africa are often consistent across populations, the specific loci affected by selective pressures more often vary across populations.

scholarly journals Ancient RNA virus epidemics through the lens of recent adaptation in human genomes

2020 ◽  
Vol 375 (1812) ◽  
pp. 20190575 ◽  
Author(s):  
David Enard ◽  
Dmitri A. Petrov
Keyword(s):  
Rna Virus ◽  
Human Populations ◽  
Evolutionary Perspective ◽  
Arms Races ◽  
Selective Pressures ◽  
The Past ◽  
1000 Genomes ◽  
Human Genomes ◽  
Different Types ◽  
Health And Disease

Over the course of the last several million years of evolution, humans probably have been plagued by hundreds or perhaps thousands of epidemics. Little is known about such ancient epidemics and a deep evolutionary perspective on current pathogenic threats is lacking. The study of past epidemics has typically been limited in temporal scope to recorded history, and in physical scope to pathogens that left sufficient DNA behind, such as Yersinia pestis during the Great Plague. Host genomes, however, offer an indirect way to detect ancient epidemics beyond the current temporal and physical limits. Arms races with pathogens have shaped the genomes of the hosts by driving a large number of adaptations at many genes, and these signals can be used to detect and further characterize ancient epidemics. Here, we detect the genomic footprints left by ancient viral epidemics that took place in the past approximately 50 000 years in the 26 human populations represented in the 1000 Genomes Project. By using the enrichment in signals of adaptation at approximately 4500 host loci that interact with specific types of viruses, we provide evidence that RNA viruses have driven a particularly large number of adaptive events across diverse human populations. These results suggest that different types of viruses may have exerted different selective pressures during human evolution. Knowledge of these past selective pressures will provide a deeper evolutionary perspective on current pathogenic threats. This article is part of the theme issue ‘Insights into health and disease from ancient biomolecules’.

scholarly journals Climate associated genetic variation in Fagus sylvatica and potential responses to climate change in the French Alps

2019 ◽  
Author(s):  
Thibaut Capblancq ◽  
Xavier Morin ◽  
Maya Gueguen ◽  
Julien Renaud ◽  
Stéphane Lobreaux ◽  
...  
Keyword(s):  
Global Warming ◽  
Genetic Variation ◽  
Fagus Sylvatica ◽  
Adaptive Landscape ◽  
Adaptive Genetic Variation ◽  
French Alps ◽  
Selective Pressures ◽  
Eastern Site ◽  
Populations At Risk ◽  
The Alps

ABSTRACTLocal adaptation patterns have been found in many plants and animals, highlighting the genetic heterogeneity of species along their range of distribution. In the next decades, global warming must induce a change in the selective pressures that drive this adaptive variation, forcing a reshuffling of the underlying adaptive allele distributions. For species with low dispersion capacity and long generation time such as trees, the rapidity of the change could imped the migration of beneficial alleles and lower their capacity to track the changing environment. Identifying the main selective pressures driving the adaptive genetic variation is thus necessary when investigating species capacity to respond to global warming. In this study, we investigate the adaptive landscape of Fagus sylvatica along a gradient of populations in the French Alps. Using a ddRAD-seq approach, we identified 7,000 SNPs from 570 individuals across 36 different sites. An RDA-derived method allowed us to identify several SNPs that were strongly associated with climatic gradients; moreover, we defined the primary selective gradients along the natural populations of F. sylvatica in the Alps. Strong effects of elevation and humidity, which contrast north-western and south-eastern site, were found and were believed to be important drivers of genetic adaptation. Finally, simulations of future genetic landscapes that used these findings predicted a severe range contraction and a shift towards higher altitudes for F. sylvatica in the Alps and allowed to identify populations at risk, which could be helpful for future management plans.

scholarly journals Ancient RNA virus epidemics through the lens of recent adaptation in human genomes

2020 ◽  
Author(s):  
David Enard ◽  
Dmitri A. Petrov
Keyword(s):  
Human Evolution ◽  
Rna Viruses ◽  
Rna Virus ◽  
Human Populations ◽  
Evolutionary Perspective ◽  
Arms Races ◽  
Selective Pressures ◽  
The Past ◽  
Human Genomes ◽  
Different Types

AbstractOver the course of the last several million years of evolution, humans likely have been plagued by hundreds or perhaps thousands of epidemics. Little is known about such ancient epidemics and a deep evolutionary perspective on current pathogenic threats is lacking. The study of past epidemics has typically been limited in temporal scope to recorded history, and in physical scope to pathogens that left sufficient DNA behind, such as Yersinia pestis during the Great Plague.Host genomes however offer an indirect way to detect ancient epidemics beyond the current temporal and physical limits. Arms races with pathogens have shaped the genomes of the hosts by driving a large number of adaptations at many genes, and these signals can be used to detect and further characterize ancient epidemics.Here, we detect the genomic footprints left by ancient viral epidemics that took place in the past ~50,000 years in the 26 human populations represented in the 1,000 Genomes Project. By using the enrichment in signals of adaptation at ~4,500 host loci that interact with specific types of viruses, we provide evidence that RNA viruses have driven a particularly large number of adaptive events across diverse human populations. These results suggest that different types of viruses may have exerted different selective pressures during human evolution. Knowledge of these past selective pressures will provide a deeper evolutionary perspective on current pathogenic threats.

scholarly journals Human variation in the shape of the birth canal is significant and geographically structured

2018 ◽  
Vol 285 (1889) ◽  
pp. 20181807 ◽  
Author(s):  
Lia Betti ◽  
Andrea Manica
Keyword(s):  
Morphological Diversity ◽  
Neutral Evolution ◽  
Human Populations ◽  
Shape Variation ◽  
Birth Canal ◽  
Neutral Genetic Diversity ◽  
A Minor ◽  
Human Birth ◽  
European Women ◽  
Oval Shape

The human birth canal shows a tight fit with the size of the neonate, which can lead to obstetric complications. This is not the case in other apes, and has been explained as the outcome of conflicting evolutionary pressures for bipedal locomotion and parturition of a highly encephalized fetus. Despite the suggested evolutionary constraints on the female pelvis, we show that women are, in fact, extremely variable in the shape of the bony birth canal, with human populations having differently shaped pelvic canals. Neutral evolution through genetic drift and differential migration are largely responsible for the observed pattern of morphological diversity, which correlates well with neutral genetic diversity. Climatic adaptation might have played a role, albeit a minor one, with populations from colder regions showing a more transversally oval shape of the canal inlet. The significant extent of canal shape variation among women from different regions of the world has important implications for modern obstetric practice in multi-ethnic societies, as modern medical understanding has been largely developed on studies of European women.

scholarly journals Neutral evolution of human enamel–dentine junction morphology

2020 ◽  
Vol 117 (42) ◽  
pp. 26183-26189
Author(s):  
Tesla A. Monson ◽  
Diego Fecker ◽  
Marc Scherrer
Keyword(s):  
Late Holocene ◽  
Tooth Development ◽  
Population History ◽  
Neutral Evolution ◽  
Human Populations ◽  
Geometric Morphometric ◽  
Human Enamel ◽  
Morphometric Analyses ◽  
Neutral Genetic Variation ◽  
Out Of Africa

Teeth have been studied for decades and continue to reveal information relevant to human evolution. Studies have shown that many traits of the outer enamel surface evolve neutrally and can be used to infer human population structure. However, many of these traits are unavailable in archaeological and fossil individuals due to processes of wear and taphonomy. Enamel–dentine junction (EDJ) morphology, the shape of the junction between the enamel and the dentine within a tooth, captures important information about tooth development and vertebrate evolution and is informative because it is subject to less wear and thus preserves more anatomy in worn or damaged specimens, particularly in mammals with relatively thick enamel like hominids. This study looks at the molar EDJ across a large sample of human populations. We assessed EDJ morphological variation in a sample of late Holocene modern humans (n= 161) from archaeological populations using μ-CT biomedical imaging and geometric morphometric analyses. Global variation in human EDJ morphology was compared to the statistical expectations of neutral evolution and “Out of Africa” dispersal modeling of trait evolution. Significant correlations between phenetic variation and neutral genetic variation indicate that EDJ morphology has evolved neutrally in humans. While EDJ morphology reflects population history, its global distribution does not follow expectations of the Out of Africa dispersal model. This study increases our knowledge of human dental variation and contributes to our understanding of dental development more broadly, with important applications to the investigation of population history and human genetic structure.

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