Genetic Admixture Research Articles

Unsupervised discovery of ancestry-informative markers and genetic admixture proportions in biobank-scale datasets

Admixture estimation plays a crucial role in ancestry inference and genome-wide association studies (GWASs). Computer programs such as ADMIXTURE and STRUCTURE are commonly employed to estimate the admixture proportions of sample individuals. However, these programs can be overwhelmed by the computational burdens imposed by the 105 to 106 samples and millions of markers commonly found in modern biobanks. An attractive strategy is to run these programs on a set of ancestry-informative SNP markers (AIMs) that exhibit substantially different frequencies across populations. Unfortunately, existing methods for identifying AIMs require knowing ancestry labels for a subset of the sample. This supervised learning approach creates a chicken and the egg scenario. In this paper, wepresent an unsupervised, scalable framework that seamlessly carries out AIM selection and likelihood-based estimation of admixture proportions.Our simulated and real data examples show that this approach is scalable to modern biobank datasets. OpenADMIXTURE, our Julia implementation of the method, is open source and available for free.

Genetic and Pomological Determination of the Trueness-to-Type of Sweet Cherry Cultivars in the German National Fruit Genebank

Genebank collections preserve many old cultivars with ancient breeding history. However, often, cultivars with synonymous or incorrect names are maintained in multiple collections. Therefore, pomological and genetic characterization is an essential prerequisite for confirming trueness-to-type of cultivars in gene bank collections. In our study, 1442 single sweet cherry (Prunus avium L.) trees of the German Fruit Genebank were evaluated according to their trueness-to-type. For this purpose, pomological analysis was performed, in which the accessions were assigned totheir historical cultivar names. The pomological identifications were based on several historical reference sources, such as fruit references from historical cherry cultivar and fruit-stone collections, as well as historical pomological literature sources. In addition, the cherry trees were genetically analyzed for cultivar identity using 16 SSR markers. Based on pomological characterization and genetic analysis for the majority of the trees (86%), cultivar authenticity could be confirmed. Most markers were highly discriminating and powerful for cultivar identification. The cherry collection showed a high degree of genetic diversity, with an expected heterozygosity He = 0.67. Generally, high genetic admixture between cultivars of different geographic origin and year of origin was obtained after STRUCTURE analysis, demonstrating the extensive exchange of genetic information between cherry cultivars in the collection over time. However, the phylogenetic tree calculated by DARwin reflected the geographic origin of selected cherry cultivars. After parentage analysis with CERVUS, paternity could not be confirmed for three cultivars, indicating the necessity of further pedigree analysis for these cultivars. The results of our study underlined the general importance of evaluating the authenticity of cultivars in genebank collections based on genetic and pomological characterization.

The genetic structure and admixture of Manchus and Koreans in northeast China

Background The fine-scale genetic profiles and population history of Manchus and Koreans remain unclear. Aim To infer a fine-scale genetic structure and admixture of Manchu and Korean populations. Subjects and methods We collected and genotyped 16 Manchus from Liaoning and 18 Koreans from Jilin province with about 700K genome-wide SNPs. We analysed the data using principal component analysis (PCA), ADMIXTURE, Fst, TreeMix, f-statistics, qpWave, and qpAdm. Results Manchus and Koreans showed a genetic affinity with northern East Asians. Chinese Koreans showed a long-term genetic continuity with Bronze Age populations from the West Liao River and had a strong affinity with Koreans in South Korea and Japan. Manchus had a different genetic profile compared with other Tungusic populations since the Manchus received additional genetic influence from the southern Chinese but didn’t have West Eurasian-related admixture. Conclusions The genetic formation of Manchus involving southern Chinese was consistent with the extensive interactions between Manchus and populations from central and southern China. The large-scale genetic continuity between ancient West Liao River farmers and Koreans highlighted the role farming expansion played in the peopling of the Korean Peninsula.

Bartter Syndrome-Related Variants Distribution: Brazilian Data and Its Comparison with Worldwide Cohorts

Background: Genetic testing is recommended for accurate diagnosis of Bartter syndrome (BS) and serves as a basis for implementing specific target therapies. However, populations other than Europeans and North Americans are underrepresented in most databases and there are uncertainties in the genotype-phenotype correlation. We studied Brazilian BS patients, an admixed population with diverse ancestry. Methods: We evaluated the clinical and mutational profile of this cohort and performed a systematic review of BS mutations from worldwide cohorts. Results: Twenty-two patients were included; Gitelman syndrome was diagnosed in 2 siblings with antenatal BS and congenital chloride diarrhea in 1 girl. BS was confirmed in 19 patients: BS type 1 in 1 boy (antenatal BS); BS type 4a in 1 girl and BS type 4b in 1 girl, both of them with antenatal BS and neurosensorial deafness; BS type 3 (CLCNKB mutations): 16 cases. The deletion of the entire CLCNKB (1–20 del) was the most frequent variant. Patients carrying the 1–20 del presented earlier manifestations than those with other CLCNKB-mutations and the presence of homozygous 1–20 del was correlated with progressive chronic kidney disease. The prevalence of the 1–20 del in this BS Brazilian cohort was similar to that of Chinese cohorts and individuals of African and Middle Eastern descent from other cohorts. Conclusion: This study expands the genetic spectrum of BS patients with different ethnics, reveals some genotype/phenotype correlations, compares the findings with other cohorts, and provides a systematic review of the literature on the distribution of BS-related variants worldwide.

Genetic diversity and structure in two epiphytic orchids from the montane forests of southern Ecuador: The role of overcollection on Masdevallia rosea in comparison with the widespread Pleurothallis lilijae.

Ecuador has a high diversity of orchids, but little is known about levels of genetic diversity for the great majority of species. Understanding how orchids might adapt to changes is crucial as deforestation and fragmentation of forest ecosystems threaten the survival of many epiphytic orchids that depend on other species, such as fungi and their host trees, for germination, growth, and establishment. Overcollection and the illegal trade are also major concerns for the survival of wild populations of orchids. Despite increasing awareness, effective interventions are often limited by a lack of data concerning the impacts that overexploitation might have. To fill this gap, we tested the effects of overcollection in the genetic diversity and structure of Masdevallia rosea, a narrow distributed epiphytic orchid historically collected in Ecuador, in comparison with the widely distributed Pleurothallis lilijae. Genotyping based on AFLPs showed reduced levels of diversity in wild populations but most especially in the overcollected, M. rosea. Overall, genetic admixture was high in P. lilijae segregating populations by altitude levels while fewer genetic groups were found in M. rosea. Genetic differentiation was low in both species. A spatial genetic structure was found in P. lilijae depending on altitude levels, while no spatial genetic structure was found in M. rosea. These results suggest different scenarios for the two species: while gene flow over long distance is possible in P. lilijae, the same seems to be unlikely in M. rosea possibly due to the low levels of individuals in the known populations. In situ and ex situ conservation strategies should be applied to protect the genetic pool in these epiphytic orchid species, and to promote the connectivity between wild populations. Adopting measures to reduce overexploitation and to understand the impacts of harvesting in wild populations are necessary to strengthen the legal trade of orchids.

HLA haplotypes and differential regional mortality caused by COVID-19 in Brazil: an ecological study based on a large bone marrow donor bank dataset.

The coronavirus disease 2019 (COVID-19) mortality rates varied among the states of Brazil during the course of the pandemics. The human leukocyte antigen (HLA) is a critical component of the antigen presentation pathway. Individuals with different HLA genotypes may trigger different immune responses against pathogens, which could culminate in different COVID-19 responses. HLA genotypes are variable, especially in the highly admixed Brazilian population. In this ecological study, we aimed to investigate the correlation between HLA haplotypes and the different regional distribution of COVID-19 mortality in Brazil. HLA data was obtained from 4,148,713 individuals registered in The Brazilian Voluntary Bone Marrow Donors Registry. COVID-19 data was retrieved from epidemiological bulletins issued by State Health Secretariats via Brazil's Ministry of Health from February/2020 to July/2022. We found a positive significant correlation between the HLA-A*01~B*08~DRB1*03 haplotype and COVID-19 mortality rates when we analyzed data from 26 states and the Federal District. This result indicates that the HLA-A*01~B*08~DRB1*03 haplotype may represent an additional risk factor for dying due to COVID-19. This haplotype should be further studied in other populations for a better understanding of the variation in COVID-19 outcomes across the world.

Abstract A072: Genetic ancestry is related to potential sources of breast cancer health disparities among Colombian women

Abstract Introduction: Socioeconomic disadvantages can contribute to breast cancer health disparities among populations. However, it has been shown that other factors related to the etiology of breast cancer and the biology of the tumor, might also act as determinants of health disparities, as they can impact the patients’ treatment. To date, the relationship between these factors with genetic ancestry in a highly admixed population from Latin-America, has not yet been explored. Based on this, we aimed to assess contributing factors to breast cancer health disparities according to genetic ancestry in Colombian patients from a national cancer reference center. Methods: We revised clinical-pathological and socioeconomic data from breast cancer patients diagnosed at the National Cancer Institute (NCI) of Colombia and classified variables into the following groups: etiology-related factors (e.g., age of diagnosis), tumor-biology factors (e.g., tumor size), and socioeconomic factors (e.g., health insurance), each of which reflects potential sources of racial/ethnic disparities of breast cancer. We also considered variables related to treatment administration (e.g., neoadjuvant therapy) as an indicator of disease management. We applied a Kruskal–Wallis test to assess differences in genetic ancestry fractions according to each of the variables distribution. Results: A total of 308 Colombian breast cancer patients were included. Etiology-related factors analysis showed higher European ancestry fraction in patients diagnosed at older ages (>50 years: 50% vs. ≤50 years: 46%, p=0.017), and with smaller tumors (<20mm: 52% vs. ≥20mm: 48%, p=0.038). Higher Indigenous American (IA) ancestry was observed in patients with HER2-positive tumors compared to HER2-negative cases (44% vs. 40%. p=0.011). Additionally, patients with higher IA ancestry were more frequently treated with neoadjuvant therapy (NAT) (43% vs. no-NAT: 40%, p=0.050). Moreover, socioeconomic variables showed that patients that benefit from the government public health insurance, known in Colombia as subsidized regime, and those who are covered under their relative’s health insurance, known as beneficiaries, have a higher IA ancestry (43% and 43%, respectively, vs. 37%, p=0.016), compared to patients that do afford their own health insurance (contributory regime in Colombia); conversely, these patients presented a higher European ancestry (55% vs. subsidized: 47% and beneficiaries: 49%, p=0.011). Conclusions: Our results indicate that genetic ancestry is related to several potential sources of breast cancer health disparities that cover from tumor-biology factors like tumor size and HER2 expression to socioeconomic determinants like health insurance affiliation regime. Consequently, it is possible that genetic ancestry may partially reflect some differences in the disease management and in healthcare attention given to breast cancer patients in Colombia. Citation Format: Silvia J. Serrano-Gómez, Laura Rey-Vargas, Lina Bejarano, Juan Carlos Mejía-Henao, Maria Carolina Sanabria-Salas. Genetic ancestry is related to potential sources of breast cancer health disparities among Colombian women [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A072.

Evolution of a hybrid zone of two willow species (Salix L.) in the European Alps analyzed by RAD-seq and morphometrics.

Natural hybridization of plants can result in many outcomes with several evolutionary consequences, such as hybrid speciation and introgression. Natural hybrid zones can arise in mountain systems as a result of fluctuating climate during the exchange of glacial and interglacial periods, where species retract and expand their territories, resulting in secondary contacts. Willows are a large genus of woody plants with an immense capability of interspecific crossing. In this study, the sympatric area of two diploid sister species, S.foetida and S.waldsteiniana in the eastern European Alps, was investigated to study the genomic structure of populations within and outside their contact zone and to analyze congruence of morphological phenotypes with genetic data. Eleven populations of the two species were sampled across the Alps and examined using phylogenetic network and population genetic structure analyses of RAD Seq data and morphometric analyses of leaves. The results showed that a homoploid hybrid zone between the two species was established within their sympatric area. Patterns of genetic admixture in homoploid hybrids indicated introgression with asymmetric backcrossing to not only one of the parental species but also one hybrid population forming a separate lineage. The lack of F1 hybrids indicated a long-term persistence of the hybrid populations. Insignificant isolation by distance suggests that gene flow can act over large geographical scales. Morphometric characteristics of hybrids supported the molecular data and clearly separated populations of the parental species, but showed intermediacy in the hybrid zone populations with a bias toward S.waldsteiniana. The homoploid hybrid zone might have been established via secondary contact hybridization, and its establishment was fostered by the low genetic divergence of parental species and a lack of strong intrinsic crossing barriers. Incomplete ecological separation and the ability of long-distance dispersal of willows could have contributed to the spatial expansion of the hybrid zone.

Association between INDELs in MicroRNAs and Susceptibility to Gastric Cancer in Amazonian Population.

Gastric cancer (GC) is a multifactorial, complex, and aggressive disease with a prevalence of one million new cases and high global mortality. Factors such as genetic, epigenetic, and environmental changes contribute to the onset and progression of the disease. Identification of INDELs in miRNA and its target sites in current studies showed an important role in the development of cancer. In GC, miRNAs act as oncogenes or tumor suppressors, favoring important cancer pathways, such as cell proliferation and migration. This work aims to investigate INDELs in the coding region of miRNAs (hsa-miR-302c, hsa-miR-548AJ-2, hsa-miR-4274, hsa-miR-630, hsa-miR-516B-2, hsa-miR-4463, hsa-miR-3945, hsa-miR-548H_4, hsa-miR-920, has-mir-3171, and hsa-miR-3652) that may be associated with susceptibility and clinical variants of gastric cancer. For this study, 301 patients with GC and 145 individuals from the control group were selected from an admixed population in the Brazilian Amazon. The results showed the hsa-miR-4463, hsa-miR-3945, hsa-miR-548H_4, hsa-miR-920 and hsa-miR-3652 variants were associated with gastric cancer susceptibility. The hsa-miR-4463 was significantly associated with clinical features of GC such as diffuse gastric tumor histological type, "non-cardia" localization region, and early onset. Our findings indicated that INDELs could be potentially functional genetic variants for gastric cancer risk.

Genetic Variability and Admixture Zones in the Italian Populations of Turkey Oak (Quercus cerris L.).

The Turkey oak (Quercus cerris L.) is widely distributed in Italy, where it is the ecologically dominant oak on sandy and acidic soil. In this work, we analysed 23 natural populations by means of eight SSR (microsatellite) markers, to obtain the first synthetic map of genetic variability for this species and to study its dispersion during the Holocene, due to the possibility that at least one refugium during the Last Glacial Maximum was in Italy. The analyses showed a good amount of genetic variability together with fair differentiation between populations, as indicated by FST = 0.059. A Bayesian analysis of the amount of admixture among populations revealed the presence of four putative gene pools of origin and a rough subdivision of the populations according to their geographic location, as confirmed by the spatial analysis. No evidence for the existence of putative refugial populations was found; however, this study paves the way for the planning of conservation strategies also with regard to the relationship between Turkey oak and other oak species in Italy.

Effects of fruit dimorphism on genetic structure and gene flow in the coastal shrub Scaevola taccada.

Plant propagules often possess specialized morphologies that facilitate dispersal across specific landscapes. In the fruit dimorphism of a coastal shrub, Scaevola taccada, individual plants produce either cork-morph or pulp-morph fruits. The former is buoyant and common on sandy beaches, whereas the latter does not float, is bird-dispersed, and is common on elevated sites such as slopes on sea cliffs and behind rocky shores. We hypothesized that beach populations bridge the heterogeneous landscapes by serving as a source of both fruit types, while dispersal is biased for the pulp morph on elevated sites within the islands and for the cork morph between beaches of different islands. Based on this hypothesis, we predicted that populations in elevated sites would diverge genetically over time due to isolation by distance, whereas beach populations would maintain high genetic similarity via current gene flow. The genetic structure and gene flow in S. taccada were evaluated by investigating genome-wide single nucleotide polymorphisms in plants from 17 sampling sites on six islands (belonging to the Ryukyu, Daito and Ogasawara Islands) in Japan. Geographical isolation was detected among the three distant island groups. Analyses within the Ryukyu Islands suggested that sandy beach populations were characterized by genetic admixture, whereas populations in elevated sites were relatively isolated between the islands. Pairwise FST values between islands were lowest between sandy beaches, intermediate between sandy beaches and elevated sites, and highest between elevated sites. Dispersal across the ocean by cork morphs is sufficiently frequent to prevent genetic divergence between beaches of different islands. Stronger genetic isolation of elevated sites between islands suggests that bird dispersal by pulp morphs is restricted mainly within islands. These contrasting patterns of gene flow realized by fruit dimorphism provide evidence that fruit characteristics can strongly mediate genetic structure.

Genetic diversity analysis in dairy cows of Nariño, southwestern Colombia

In Colombia, different dairy breeds were introduced from Europe and the United States, which underwent different crossing and selection processes that generated specific qualities or differences and which likely have their own genomic structure. To characterize genetic diversity, population structure, and admixture, we used genotypes from 23,182 autosomal single nucleotide polymorphisms (SNPs) of 130 animals representing four dairy cattle breed groups from Nariño. In addition, we merged genotypes from 43,043 autosomal SNPs, from 137 animals from the Decker database (Decker et al., 2014) (DRYAD doi:10.5061/dryad.th092). After the quality control process of pruning the merged dataset, we were left with 7,475 autosomal SNPs shared by both databases of Nariño (127 samples) and Decker (135 samples). Genetic diversity levels were moderate in all breeds (average observed heterozygosity = 0.40). Based on the fixation index values, we conclude that Brahman individuals were more differentiated than the taurine breeds (-0.374 to 0.076 for Brown Swiss). Pairs between taurine breeds showed low genetic differentiation (0.011-0.479). Principal component analysis revealed that in both the Nariño and Decker databases, the taurine formed the most compact cluster compared with other breeds known not to share the same ancestry, and Jersey, Brown Swiss, and Normand individuals exhibited high similarity with Holstein individuals. Hierarchical cluster analysis with Admixture revealed that Brahman, Jersey, Normand, and Holstein from the Decker databases most of which were clustered together with the dairy breeds of the Nariño highland tropics are not able to create different groups, thus having greater similarity with each other. This can be explained by the crosses made by farmers to increase milk production volume, always based on the Holstein breed with semen of bulls from America and Canada. Detrimental impacts due to intensive selection might cause some specific traits from the region to be fixed in the offspring, which can influence their adaptive capacity to the highland tropics.

Challenges in selecting admixture models and marker sets to infer genetic ancestry in a Brazilian admixed population

The inference of genetic ancestry plays an increasingly prominent role in clinical, population, and forensic genetics studies. Several genotyping strategies and analytical methodologies have been developed over the last few decades to assign individuals to specific biogeographic regions. However, despite these efforts, ancestry inference in populations with a recent history of admixture, such as those in Brazil, remains a challenge. In admixed populations, proportion and components of genetic ancestry vary on different levels: (i) between populations; (ii) between individuals of the same population, and (iii) throughout the individual's genome. The present study evaluated 1171 admixed Brazilian samples to compare the genetic ancestry inferred by tri-/tetra-hybrid admixture models and evaluated different marker sets from those with small numbers of ancestry informative markers panels (AIMs), to high-density SNPs (HDSNP) and whole-genome-sequence (WGS) data. Analyses revealed greater variation in the correlation coefficient of ancestry components within and between admixed populations, especially for minority ancestral components. We also observed positive correlation between the number of markers in the AIMs panel and HDSNP/WGS. Furthermore, the greater the number of markers, the more accurate the tri-/tetra-hybrid admixture models.

TSLP and IL25 variants are related to asthma and atopy

Asthma is a chronic inflammatory disease that affects millions of people worldwide. There are several phenotypes and endophenotypes of this condition, and some are associated with increased eosinophil counts in blood and sputum. Studies have shown that severe asthma may be associated with genes related to type 2 innate lymphoid cells (ILC2). This study evaluated the association between ILC2-related gene variants (TSLP and IL25) with asthma endophenotypes and atopy markers. Individuals belonging to the Programa para Controle da Asma na Bahia (ProAR) cohort were diagnosed according to the Global Initiative for Asthma (GINA) criteria, and divided into three subgroups: controls with no asthma, mild to moderate asthma (MMA), and severe asthma (SA). Blood collection, DNA extraction, genotyping, blood count, total IgE dosage, and cytokine dosage were performed. Logistic regression models were conducted for the association analysis. We found significant protective associations between the alternative alleles of variants in the TSLP gene with asthma and its severity. Notably, rs10062929 (A), rs11466741 (T), and rs149540660 (T) were related to eosinophil counts, IgE levels, and cytokine levels of our patients. We found significant associations between IL25 gene variants with asthma endophenotypes and atopy markers. The rs10143597 (G) and rs3811178 (G) showed a protective association against atopy. We also evaluated the in silico expression levels of these variants in lung tissue, skin, and fibroblast culture. Our results indicate that variants in these genes may regulate atopy, asthma, and their different endophenotypes in an admixed Brazilian population.

The threshold value for identifying insulin resistance (HOMA-IR) in an admixed adolescent population: A hyperglycemic clamp validated study.

To validate the homeostasis model assessment (HOMA) of insulin resistance (IR) as a surrogate to the hyperglycemic clamp to measure IR in both pubertal and postpubertal adolescents, and determine the HOMA-IR cutoff values for detecting IR in both pubertal stages. The study sample comprised 80 adolescents of both sexes (aged 10-18 years; 37 pubertal), in which IR was assessed with the HOMA-IR and the hyperglycemic clamp. In the multivariable linear regression analysis, adjusted for sex, age, and waist circumference, the HOMA-IR was independently and negatively associated with the clamp-derived insulin sensitivity index in both pubertal (unstandardized coefficient - B = -0.087, 95% confidence interval [CI] = -0.135 to -0.040) and postpubertal (B = -0.101, 95% CI, -0.145 to -0.058) adolescents. Bland-Altman plots showed agreement between the predicted insulin sensitivity index and measured clamp-derived insulin sensitivity index in both pubertal stages (mean =-0.00 for pubertal and postpubertal); all P > 0.05. The HOMA-IR showed a good discriminatory power for detecting IR with an area under the receiver operator characteristic curve of 0.870 (95% CI, 0.718-0.957) in pubertal and 0.861 (95% CI, 0.721-0.947) in postpubertal adolescents; all P < 0.001. The optimal cutoff values of the HOMA-IR for detecting IR were > 3.22 (sensitivity, 85.7; 95% CI, 57.2-98.2; specificity, 82.6; 95% CI, 61.2-95.0) for pubertal and > 2.91 (sensitivity, 63.6; 95% CI, 30.8-89.1, specificity, 93.7; 95%CI, 79.2-99.2) for postpubertal adolescents. The threshold value of the HOMA-IR for identifying insulin resistance was > 3.22 for pubertal and > 2.91 for postpubertal adolescents.

Discovery of genomes of Neanderthal, Denisova and its impact on modern human

<p indent="0mm">The 2022 Nobel Prize in Physiology or Medicine was surprisingly awarded to Svante Pääbo for his establishment of a novel discipline, paleogenomics. Paleogenomics offers a potent means of understanding the course of modern human evolution. Pääbo’s research lays a solid foundation for answering the question of what makes us, Homo sapiens, different from other hominins. This year’s Nobel laureate has observed genetic admixture in different groups of archaic humans, and found that parts of the genetic code of these extinct branches of the human evolutionary tree are present in the genomes of modern humans, influencing us both physiologically and pathologically. In this paper, Pääbo’s research findings are first summarized to deepen, consolidate, and broaden the understanding of extinct hominins and paleogenomics. Pääbo’s team was responsible for the first draft sequence of the Neanderthal genome, showing that between 1.5% and 2.1% of modern Eurasian genomes are derived from Neanderthals. They followed this with the complete Neanderthal genome sequence. Similarly, Pääbo and colleagues published both the first draft and the complete sequence of the Denisovan genome. They found evidence of genetic admixture between the Denisovans and modern humans, showing that the genomes of people in Oceania are between 3% and 6% Denisovan while the figure for people in Asia is about 0.2%. Furthermore, at least 0.5% of the Denisovan genome was derived from the Neanderthals. The COVID-19 pandemic provided evidence of the good and bad qualities of the Neanderthal inheritance, particularly in relation to the immune systems of modern humans. A gene cluster on chromosome 3 that was inherited from Neanderthals was found to be associated with severe COVID-19. This gene cluster is mainly found in modern humans from the Middle East and southern Asia. Several genes included in this cluster have been demonstrated to play a role in immune functions and may be involved in the infection process of SARS-CoV-2. Interestingly, a gene segment on chromosome 12 which was also inherited from Neanderthals is protective against severe COVID-19. This gene segment is mainly distributed in inhabitants of Europe, Asia, and the Americas, but not of Africa and Oceania. This segment contains the OAS1 gene which encodes proteins that activate enzymes that are important during RNA-viral infections. This is part of the reason why carrying this gene segment can reduce the risk of developing severe COVID-19. The Neanderthals have contributed many immune-related genes to modern humans, including the well-documented cluster containing the TLR1, TLR6, and TLR10 genes. TLR1, TLR6, and TLR10 gene haplotypes inherited from Neanderthals show high expression frequencies in the genomes of Europeans and Asians. These three genes play important roles in the innate immune system that is the first line of defense against pathogens and can trigger adaptive immunity. The TLR1, TLR6, and TLR10 haplotypes increase the expression of their encoded proteins, which not only enhances innate immunity but can also induce hypersensitivity resulting in allergy. Lastly, the way in which Denisovan genes affect Tibetan and Nepalese people to adapt to the extreme conditions of the Qinghai-Tibet Plateau and the Himalayas, respectively, are discussed. The EPAS1 gene in Tibetans and Nepalese is inherited from the Denisovans and encodes the hypoxia-inducible factor HIF-2α, a transcription factor involved in the body’s response to low-oxygen conditions. That is to say, both Tibetan and Nepalese people are well adapted to hypoxic and cold conditions thanks to a gene inherited from the Denisovans. This paper intends to inspire more research into extinct hominins and paleogenomics, which can enhance our knowledge of certain diseases, allowing the development of new beneficial therapeutic targets. Thus, surprising results in a new field will eventually reap great benefits.

The Peruvian Alzheimer Disease Initiative (PeADI): An international effort model to increase diversity in AD research

AbstractBackgroundPeru is one of the five largest countries in Latin America and harboring a high Amerindian ancestry component in this population. The Latin American population, including Peruvians, are underrepresented in research studies of Alzheimer disease (AD).We have developed an international collaborative research initiative to ascertain a Peruvian cohort for AD and other related dementias for genetic studies of Amerindian individuals.MethodsThe Peruvian Alzheimer Disease initiative (PeADI) was developed to recruit and enroll Peruvian adults aged 65 and older to a comprehensive genetic AD study. Individuals will get whole genome sequencing and plasma biomarkers. Participants included cases with AD and ADD,healthy controls as well as multiplex AD families. Since 2019, we have established a multisource ascertainment approach including recruitment at main hospitals, outreach community activities and more recently due to the COVID19 pandemic remote recruitment and home visits. Our recruitment has expanded since our initial efforts in which we enrolled individuals from Lima, the capital city. We are now ascertaining participants in three regions from the Andes highlands (Puno,Huancayo, and Cusco) and one region from the southern coast (Tacna).All participants are enrolled using a standard protocol administered by neurologists and neuropsychologists. This protocol includes clinical interviews and neurocognitive assessment.ResultsAs of December 2021, we have enrolled 103 AD and other dementia cases, 202 controls and 4 multiplex AD families. While the majority of participants are from Lima, 25% controls and 1% of cases have been recruited in regions outside Lima. We have confirmed a significant association between APOE and AD in Peruvian Population higher than we have observed in non‐Hispanics. In addition to ascertainment activities, we are working closely with the respective sites to develop a network for AD research across Peru. To date, we have developed local research capacities within each region,including training opportunities for investigators, coordinators and lab technicians. In addition, we are developing resources for health and medical support and basic equipment for all regions.ConclusionThe PeADI study shows the importance of equitable international north‐south cooperation and local network cooperation to increase representation of understudied admixed populations to help us understand Amerindian ancestry in drug target discovery.

New insights on patterns of genetic admixture and phylogeographic history in Iberian high mountain populations of midwife toads.

Multiple Quaternary glacial refugia in the Iberian Peninsula, commonly known as "refugia within refugia", allowed diverging populations to come into contact and admix, potentially boosting substantial mito-nuclear discordances. In this study, we employ a comprehensive set of mitochondrial and nuclear markers to shed light onto the drivers of geographical differentiation in Iberian high mountain populations of the midwife toads Alytes obstetricans and A. almogavarii from the Pyrenees, Picos de Europa and Guadarrama Mountains. In the three analysed mountain regions, we detected evidence of extensive mito-nuclear discordances and/or admixture between taxa. Clustering analyses identified three major divergent lineages in the Pyrenees (corresponding to the eastern, central and central-western Pyrenees), which possibly recurrently expanded and admixed during the succession of glacial-interglacial periods that characterised the Late Pleistocene, and that currently follow a ring-shaped diversification pattern. On the other hand, populations from the Picos de Europa mountains (NW Iberian Peninsula) showed a mitochondrial affinity to central-western Pyrenean populations and a nuclear affinity to populations from the central Iberian Peninsula, suggesting a likely admixed origin for Picos de Europa populations. Finally, populations from the Guadarrama Mountain Range (central Iberian Peninsula) were depleted of genetic diversity, possibly as a consequence of a recent epidemic of chytridiomycosis. This work highlights the complex evolutionary history that shaped the current genetic composition of high mountain populations, and underscores the importance of using a multilocus approach to better infer the dynamics of population divergence.

Genetic and socioeconomic modulation of biomarkers

AbstractIntroductionIdentification and measurement of biomarkers has become a key component of much research in the neurodegeneration field, particularly in research linking psychosocial stressors and brain health. Socioeconomic position may influence neurodegeneration through several pathways, including behaviors and psychosocial stress levels, both of which may influence biological markers of inflammation, coagulation, and adhesion. Underserved populations, particularly from low‐to‐middle‐income countries in Latin America (LMICs), are more likely to have experienced poor, chronic stress due to discrimination, limited educational and occupational opportunities, and minimal access to social support and health care. All of these factors can modify neurodegenerative disease risk and clinical progression of dementia, in part through changes in immune function. Complicating matters, few studies have characterized inflammatory biomarker levels in LMICs, where biological and environmental exposures likely modify immune profiles. Finally, the effect of complex genetic admixture on both baseline and disease‐associated inflammatory biomarker levels remains underexplored, greatly limiting the generalizability of dementia biomarkers (beta amyloid, tau, neurofilament) that were largely developed in homogenous populations.MethodWe propose to review the existing evidence and present our ongoing study fostered in the Multi‐Partner Consortium to Expand Dementia Research in Latin America (ReDLat) cohort divided into three groups: participants with Alzheimer´s Dementia (AD), participants with Frontotemporal Dementia (FTD), and controls. We will comprehensively assess gene and protein expression measures of immune function in blood to identify single and combined measurements that provide sensitive and specific distinction between AD and FTD and all cases from controls. In addition, we will assess the modulatory effect that social determinants of health (SDOH) have on these biological biomarkers.Expected ResultsOur expected outcome is to understand how SDOH contribute to gene and protein expression measures of immune function and how they modify the gold standard biomarkers of disease and risk for AD and FTD in Latin America.ConclusionsNew opportunities for identifying novel diagnostic and therapeutic inroads may be easier to detect in Latin American populations that display a greater environmental and genomic diversity, while simultaneously elucidating potential strategies for reducing health disparities in Americans who face similar SDOH challenges.

An isolated crested newt population in Dutch coastal dunes: distribution relict or introduction?

Abstract Isolated distribution patches may represent local remnants of a formerly wider range or could have originated by human-mediated expansion beyond the natural range. Distinguishing between these two scenarios is not always straightforward. Northern crested newts (Triturus cristatus) in the Dutch coastal dunes are disconnected from the main species range by over 40 kilometres and whether they have been present historically is unclear. We genotyped crested newts from throughout the Netherlands for an mtDNA marker to determine the provenance of the coastal dune population. Because a closely related species, the Italian crested newt (T. carnifex), has an introduction history in the Netherlands, we also screened eight nuclear DNA SNP markers diagnostic for T. cristatus vs. T. carnifex. The crested newts from the coastal dunes carry a single T. cristatus mtDNA haplotype that naturally occurs in the south, but not the east, of the Netherlands. Therefore, we cannot distinguish if the population represents a natural distribution relict or is derived from an introduction. We find no evidence of genetic admixture with T. carnifex in the coastal dunes, but such admixture is apparent at another Dutch locality (far removed from a previously known genetically admixed population). Our study illustrates how difficult it can be to determine the origin of isolated populations.