Genetic Admixture Research Articles

Molecular and morphological evidence of hybridization between two dimorphic sympatric species of Fuchsia (Onagraceae).

Hybridization is commonly reported in angiosperms, generally based on morphology, and in few cases confirmed by molecular markers. Fuchsia has a long tradition of ornamental cultivars with different hybrids produced by artificial crosses, so natural hybridization between sympatric Fuchsia species could be common. Natural hybridization between F. microphylla and F. thymifolia was tested using six newly developed microsatellites for F. microphylla in addition to other molecular markers with codominant and maternal inheritance. Geometric morphometrics of leaves and floral structures were also used to identify putative hybrids. Hybrids showed a different degree of genetic admixture between both parental species. Chloroplast DNA (cpDNA) sequences indicated that hybridization occurs in both directions, in fact, some of the hybrids showed new haplotypes for cpDNA and ITS (internal transcriber spacer of nuclear ribosomal RNA genes) sequences. The morphology of hybrid individuals varied between the two parental species, but they could be better identified by their leaves and floral tubes. Our study is the first to confirm the hybridization in natural populations of Fuchsia species and suggests that hybridization has probably occurred repeatedly throughout the entire distribution of the species. Phylogeographic analysis of both species will be essential to understanding the impact of hybridization throughout their complete distribution.

Whole-exome sequencing reveals novel variants of monogenic diabetes in Tunisia: impact on diagnosis and healthcare management.

Introduction: Monogenic diabetes (MD) accounts for 3%-6% of all cases of diabetes. This prevalence is underestimated due to its overlapping clinical features with type 1 and type 2 diabetes. Hence, genetic testing is the most appropriate tool for obtaining an accurate diagnosis. In Tunisia, few cohorts of MD have been investigated until now. The aim of this study is to search for pathogenic variants among 11 patients suspected of having MD in Tunisia using whole-exome sequencing (WES). Materials and methods: WES was performed in 11 diabetic patients recruited from a collaborating medical center. The pathogenicity of genetic variation was assessed using combined filtering and bioinformatics prediction tools. The online ORVAL tool was used to predict the likelihood of combinations of pathogenic variations. Then, Sanger sequencing was carried out to confirm likely pathogenic predicted variants among patients and to check for familial segregation. Finally, for some variants, we performed structural modeling to study their impact on protein function. Results: We identified novel variants related to MD in Tunisia. Pathogenic variants are located in several MODY and non-MODY genes. We highlighted the presence of syndromic forms of diabetes, including the Bardet-Biedl syndrome, Alström syndrome, and severe insulin resistance, as well as the presence of isolated diabetes with significantly reduced penetrance for Wolfram syndrome-related features. Idiopathic type 1 diabetes was also identified in one patient. Conclusion: In this study, we emphasized the importance of genetic screening for MD in patients with a familial history of diabetes, mainly among admixed and under-represented populations living in low- and middle-income countries. An accurate diagnosis with molecular investigation of MD may improve the therapeutic choice for better management of patients and their families. Additional research and rigorous investigations are required to better understand the physiopathological mechanisms of MD and implement efficient therapies that take into account genomic context and other related factors.

Genetic Ancestry-specific Molecular and Survival Differences in Admixed Patients With Breast Cancer.

We aim to determine whether incremental changes in genetic ancestry percentages influence molecular and clinical outcome characteristics of breast cancer in an admixed population. Patients with breast cancer are predominantly characterized as "Black" or "White" based on self-identified race/ethnicity or arbitrary genetic ancestry cutoffs. This limits scientific discovery in populations that are admixed or of mixed race/ethnicity as they cannot be classified based on historical race/ethnicity boxes or genetic ancestry cutoffs. We used The Cancer Genome Atlas cohort and focused on genetically admixed patients that had less than 90% European, African, Asian, or Native American ancestry. Genetically admixed patients with breast cancer exhibited improved 10-year overall survival relative to those with >90% European ancestry. Within the luminal A subtype, patients with lower African ancestry had longer 10-year overall survival compared to those with higher African ancestry. The correlation of genetic ancestry with gene expression and DNA methylation in the admixed cohort revealed novel ancestry-specific intrinsic PAM50 subtype patterns. In luminal A tumors, genetic ancestry was correlated with both the expression and methylation of signaling genes, while in basal-like tumors, genetic ancestry was correlated with stemness genes. In addition, we took a machine-learning approach to estimate genetic ancestry from gene expression or DNA methylation and were able to accurately calculate ancestry values from a reduced set of 10 genes or 50 methylation sites that were specific for each molecular subtype. Our results suggest that incremental changes in genetic ancestry percentages result in ancestry-specific molecular differences even between well-established PAM50 subtypes which may influence disparities in breast cancer survival outcomes. Accounting for incremental changes in ancestry will be important in future research, prognostication, and risk stratification, particularly in ancestrally diverse populations.

Microsatellites reveal divergence in population genetic diversity, and structure of osyris lanceolata (santalaceae) in Uganda and Kenya

BackgroundOsyris lanceolata (Hochst. & Steud.) (Santalaceae) is a multipurpose plant highly valued culturally and economically in Africa. However, O. lanceolata populations have rapidly dwindled in East Africa due to overexploitation and this is believed to cause further consequences on the species’ genetic diversity and structure within the region. Information regarding a species’ genetic diversity and structure is necessary for conservation but this is currently lacking for O. lanceolata in Uganda and Kenya. Lack of adequate scientific data hinders conservation efforts hence threatening the species survival and livelihoods. This study investigated patterns in genetic diversity and structure of O. lanceolata in Uganda and Kenya. Ten polymorphic microsatellite loci were used to genotype 210 individuals: 96 from Ugandan and 114 from Kenyan populations.ResultsAll populations were highly polymorphic (80–100% polymorphism). A genetic differentiation was found between Kenyan and Ugandan populations. The highest genetic differentiation was among individuals and the least among populations. The Kenyan populations showed higher genetic diversity than Ugandan populations. The Ugandan populations showed more marker deviations from Hardy-Weinberg equilibrium and inbreeding coefficient. Two populations showed evidence of going through a recent bottleneck. There was significant genetic differentiation and structuring at higher K values into larger clusters and observed admixture between populations. The populations were significantly isolated by altitude as opposed to distance and climatic variables. Main barriers were associated with altitude differences. The data supports the idea of long-distance gene-flow between high altitude populations in both countries.ConclusionThe divergence in genetic structure suggests unrecognised taxonomic units within O. lanceolata which are characteristic to lower altitudes and higher altitudes including most Kenyan populations with divergent evolutionary patterns. Geographical barriers and environmental gradients could have influenced this genetic divergence, and such patterns may escalate the species microevolutionary processes into full allopatric speciation. Further investigations into the species’ genetic admixture and emerging taxonomic units are necessary to guide conservation strategies in the region.

Patterns of admixture and introgression in a mosaic Mytilus galloprovincialis and Mytilus edulis hybrid zone in SW England.

The study of hybrid zones offers important insights into speciation. Earlier studies on hybrid populations of the marine mussel species Mytilus edulis and Mytilus galloprovincialis in SW England provided evidence of admixture but were constrained by the limited number of molecular markers available. We use 57 ancestry-informative SNPs, most of which have been mapped genetically, to provide evidence of distinctive differences between admixed populations in SW England and asymmetrical introgression from M. edulis to M. galloprovincialis. We combine the genetic study with analysis of phenotypic traits of potential ecological and adaptive significance. We demonstrate that hybrid individuals have brown mantle edges unlike the white or purple in the parental species, suggesting allelic or non-allelic genomic interactions. We report differences in gonad development stage between the species consistent with a prezygotic barrier between the species. By incorporating results from publications dating back to 1980, we confirm the long-term stability of the hybrid zone despite higher viability of M. galloprovincialis. This stability coincides with a dramatic change in temperature of UK coastal waters and suggests that these hybrid populations might be resisting the effects of global warming. However, a single SNP locus associated with the Notch transmembrane signalling protein shows a markedly different pattern of variation to the others and might be associated with adaptation of M. galloprovincialis to colder northern temperatures.

Pig-Typical Gene Pool Characteristics in Wild Boars from Vojvodina, Serbia: A Study of Genetic Diversity, Differentiation, Assignment, and Admixture

Summary The aim of this study was to examine whether and to what extent wild boars, Sus scrofa, from Vojvodina, Serbia, exhibited pig-typical gene pool characteristics. We used 16 microsatellite markers that have already been proven to distinguish between wild boars from eastern Austria and pigs. We screened genotypes of 21 wild boars from Vojvodina, 20 Mangulica (Serbian Managaliza) and 4 Hungarian Mangaliza as well as 48 commercial slaughter pig (CSP) samples. The wild boars exhibited relatively high genetic diversity, but no significant spatial structuring across Vojvodina. Our analyses of factorial correspondence, Bayesian assignment, as well as genetic structure and admixture demonstrated a clear distinction between wild boars, Mangulica, Hungarian Mangaliza, and CSPs. The latter were characterized by admixture of variable portions of six genetic clusters, while wild boars, Mangulica, and Hungarian Mangaliza were characterized largely by single genetic clusters, respectively; that finding was in strong contrast to earlier results showing presence of several genetic clusters in Austrian wild boars but only one cluster in CSPs. Two (9.5%) of the wild boar samples were massively introgressed by CSPs (or represented pig samples, possibly due to sample confusion). All wild boars harbored at least very small portions of pig-typical gene pool characteristics, supposedly representing signals of historical introgressions or incomplete gene pool differentiation during domestication. Mangulica-typical signals were also found in the wild boars, but at a significantly lower level than CSP-signals. A more comprehensive data set may reveal possible hot spots of introgression by Mangulica or CSPs in wild boars from Vojvodina, particularly when accompanied by other molecular markers, such as mitochondrial and nuclear DNA sequences or SNPs.

Hi‐C analysis in frontal cortex using local ancestry identifies ancestry‐specific chromatin 3D interactions

AbstractBackgroundGenetic risk for Alzheimer Disease (AD) varies across populations with different ancestry. Three‐dimensional (3D) genome architecture regulates gene transcription. Genome‐wide Hi‐C analyses have revealed dynamic 3D genome changes during development and disease progression. The variation of 3D genome architecture on different ancestral background, however, has not been extensively studied, especially at high‐resolution level. Recently, we developed the DeepLoop pipeline enabling robust high‐resolution analysis. We applied DeepLoop to characterize 3D genome architecture in frontal cortex from African American (AA) and European (EU) donors while considering local ancestry (LA) in admixed samples.MethodsHi‐C libraries were constructed and ∼500 million of paired‐end reads were obtained in 8 samples (4 AA and 4EU) that were sex‐matched and homozygous for APOEε4. We partitioned Hi‐C data into compartment A (open and transcriptionally active chromatin) and compartment B (compacted and transcriptionally silenced chromatin). In total, 6206 compartment bins across the genome were compared at a 500kb resolution. DeepLoop was used to call chromatin loop (often represents promoter‐enhancer interaction) at a 5kb‐resolution. LA was calculated using RFMix with SNP‐array data and a reference panel from 1000 Genomes for EU, African (AF) and Amerindian (AI) ancestry.ResultsMost of the A and B compartments were consistent among individuals with only <5% of them switched between AA and EU individuals. The EU samples have slightly (107 bins) more transcriptionally active bins than the AA samples. While many of homozygous LA blocks displayed same chromatin loop pattern between and within ancestries, we did observe ancestry‐specific loop as well as differences between individuals of the same ancestry. Importantly, the presence of heterozygous LA (African/EU) at some loci displayed a composite loop pattern that was present in the same region of homozygous LA of African or EU ancestry.ConclusionThe 3D genome architecture can be variable between different ancestral backgrounds as well as between individuals of the same LA. We hypothesize that admixture of LA can create novel or demolish chromatin interactions observed in the homozygous LA. These data emphasize the importance of LA in identifying the causal loci contributing to AD in admixed population such as AF and Hispanic/Latino.

Abstract B147: The relationship between germline variants and clinicopathological characteristics in triple negative breast cancer patients from Colombia

Abstract Introduction: Triple-negative breast cancer (TNBC) is the molecular subtype with the worst prognosis among breast tumors. It has been shown that the presence of germline variants can influence disease onset, progression, tumor biology, and other outcomes, however, to this date, the differences in clinical-pathological features according to germline variants in an admixed population like Colombian women, have not been yet explored. Therefore, the aim of this study was to explore the relationship between clinical-pathological characteristics and germline mutations in TNBC patients from Colombia. Methodology: This is a descriptive analysis that included 47 Colombian women with confirmed diagnosis of hereditary TNBC treated at the National Cancer Institute of Colombia, from 2008 to 2022. Germline mutations in 105 genes were assessed using the TruSigth multi-gene panel, and patients were divided according to the identified mutation into the following groups: BRCA1 carriers (n=18), BRCA2 carriers (n=13), homologous recombination (HR) gene carriers (n=13), and carriers of mutations in other genes (n=3). Fisher’s and Pearson’s chi-squared tests were used for categorical variables, and differences were considered statistically significant if p<0.05. Results: Among our cohort, the identified mutation with the highest prevalence was the c.5123C>A p. (Ala1708Glu) in the BRCA1 gene (36,9%). Regarding clinical-pathological features, we observed statistically significant differences in the distribution of germline mutations by age at diagnosis (p=0.042), body mass index (BMI) (p=0.04), and tumor differentiation (p=0.01). Women younger than 50 years at diagnosis had the highest frequency of BRCA1 (23,9%) mutations. Overweight (BMI: 25-30) and obese (BMI>30) patients presented a higher proportion of mutations in the BRCA1 (15,2%) and BRCA2 (13,0%) genes, compared to patients with mutations in HR repair pathways (8,6%) and mutations in other genes (2,2%). This is interesting as previous reports have shown an association between BRCA1/2 mutations with BMI and chronic inflammation, which could influence the development and progression of breast cancer. Poorly differentiated tumors (Bloom-Richardson: III) were more frequently observed in patients with BRCA1 mutations (32,6%), followed by patients with mutations in the HR genes (17,4%). It is possible that this is related to the genetic changes that germline mutations induce within the tumor, which ultimately lead to a less differentiated disease. Conclusion: Our study confirms the greater proportion of mutations in BRCA1/2 genes in TNBCs among the Colombian population. The characterization of clinical-pathological characteristics of germline mutation-related tumors may help improve diagnosis, prognosis assessment, and targeted therapeutic approaches. Further studies with larger patient cohorts are needed to confirm our findings. Additionally, large-scale studies are also warranted to elucidate the landscape of germline mutations relevant to the Colombian population, along with its clinical implications. Citation Format: Yina Tatiana Zambrano Ordonez, Laura Rey Vargas, Paula Daniela Morales, Silvia Juliana Serrano. The relationship between germline variants and clinicopathological characteristics in triple negative breast cancer patients from Colombia [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B147.

Abstract B044: Avanzando Caminos (Leading Pathways): The Hispanic/Latino cancer survivorship cohort study

Abstract Background: Advances in prevention, early detection, and treatment have resulted in a 29% reduction in cancer mortality since 1990 and unprecedented increases in the number of cancer survivors. There are more than 16.9M survivors living in the US today and 22.1M are expected by 2030. Cancer survivorship outcomes vary by race/ethnicity, socioeconomic status (SES), and more. Cancer is the leading cause of deaths in Hispanics/Latinos (H/Ls), a critical issue given that H/Ls are the largest ethnic minority group in the US and will account for 30% of the US population by 2060. H/Ls are disproportionately impacted by cancer due to inequities in SES and healthcare access, which leads to differences in risk factors/exposures and barriers to high-quality cancer prevention, early detection, and treatment. Although H/Ls have lower incidence rates for most common cancer types, significant disparities exist in prevalence, invasiveness, and mortality in specific cancers and across multiple patient-reported outcomes, such as quality of life and symptom burden. However, there is limited work documenting survivorship experiences among H/Ls. Purpose: The Avanzando Caminos multisite cohort study was established to address critical gaps in the science of H/L survivorship. It aims to examine the influence of sociocultural, medical, stress, psychosocial, lifestyle, behavioral, and biological factors on symptom burden, health-related quality of life, and clinical outcomes among H/Ls who have been previously treated for cancer. Methods: Avanzando Caminos, a collaboration between the Sylvester Comprehensive Cancer Center at the University of Miami and the Mays Cancer Center at UT Health San Antonio, is a 6-year prospective, cohort-based study of 3,000 H/Ls (1,500 in South Florida and 1,500 in South Texas) who completed primary cancer treatment within the past five years for stomach, liver, cervical, colorectal, lung, breast, kidney, or prostate cancers. Participants will complete self-report measures at baseline, 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years. Blood draws to assess leukocyte gene expression, cardiometabolic markers, and genetic admixture will be collected at baseline, 1 year, 3 years, and 5 years. Medical and cancer characteristics and clinical outcomes will be extracted from the electronic medical record and/or state cancer registry at each time point. Data analysis will include general latent variable modeling with maximum likelihood robust variance estimation. Results: So far, we have recruited 398 H/L participants with a mean age of 59.49 years, 62% are female, 35% are Mexican, 57% Cuban, 24% Central/South American, 78% Puerto Rican, and 7% other. Preliminary results will include sociocultural, quality of life, stress, and other factors impacting H/Ls survivors. Conclusions: Avanzando Caminos is expected to fill critical gaps in knowledge to guide future secondary and tertiary prevention efforts to mitigate cancer disparities and optimize health-related quality of life among Hispanic/Latino cancer survivors. Citation Format: Amelie G. Ramirez, Patricia Chalela, Stephanie Rowan, Ysabel R. Lew, Victoria C. Garza, Natalie Rodriguez, Myriam N. Gonzalez, Britney E. Ortiz, Dorothy Long Parma, Edgar Muñoz, Yidong Chen, Chen-Pin Wang, Adolfo E. Diaz Duque, Luz M. Garcini, Dolores M. Perdomo, Stefanie V. Beltran, Gabrielle Montes de Oca, Maria Baraya, Akina Natori, Madeline H. Krause, Paulo S. Pinheiro, Patricia I. Moreno, Michael H. Antoni, Carmen Calfa, Olveen Carrasquillo, Gilberto Lopes, Steve Cole, Frank J. Penedo. Avanzando Caminos (Leading Pathways): The Hispanic/Latino cancer survivorship cohort study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B044.

Abstract B063: Association of genetic ancestry with all-cause mortality and cancer mortality among Black and White individuals in the PLCO cohort

Abstract Introduction: It is unknown how much of the increased all-cause mortality and cancer mortality risk in Black individuals is due to race as a social construct versus biological factors such as genetic ancestry. We examined the association of genetic ancestry with all-cause mortality and cancer mortality, controlling for risk factors and self-reported race/ethnicity, in the PLCO cohort. Methods: We used PLCO data from 154,887 participants, including 7,708 Black individuals and 137,562 White individuals. Genetic ancestry was determined by GRAF (https://github.com/ncbi/graf) on a set of 10,000 pre-selected fingerprinting variants. Percent ancestry for each of Europe, Africa, and East-Asia was determined for each person. We fit Cox models for time to death or time to cancer death, controlling for smoking history and other risk factors. Results: Self-reported Black individuals had increased all-cause mortality (HR=1.27, 95%CI: 1.19-1.35, p<0.0001) and cancer mortality (HR=1.25 95%CI: 1.12-1.40, p<0.0001) versus self-reported White individuals. For White individuals, increases in European ancestry were associated with increased death risk, (HR=1.01 per 1% increase in European ancestry, 95% CI:1.01-1.02, p=0.0003) and cancer mortality (HR=1.01, 95%CI:1.00-1.02, p=0.02). For Black individuals, increases in African ancestry were also associated with increased death risk, (HR=1.01 per 1% increase in African ancestry, 95%CI: 1.00-1.01, p=0.01) and cancer mortality (HR=1.01, 95%CI: 1.00-1.04, p=0.13), although not statistically significant. Conclusions: For self-reported White individuals, increasing European ancestry was associated with an increased all-cause mortality and cancer mortality risk. For self-reported Black individuals, there was evidence that increasing African ancestry increases all-cause mortality risk, but not cancer mortality. However, associations with ancestry were small and may be vulnerable to residual confounding. Impact/Significance: A mechanistic explanation for this finding is unclear, but it could be related to population genetic “fitness” with reduced genetic admixture leading to decreased fitness for survival. Citation Format: Courtney D. Dill, Dontray Crump, Rebecca Landy, Li Cheung, Wen-Yi Huang, Sonja Berndt, Neal Freedman, Hormuzd Katki. Association of genetic ancestry with all-cause mortality and cancer mortality among Black and White individuals in the PLCO cohort [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B063.

Genetic ancestry of human induced pluripotent stem cells banked for neurodegeneration research

AbstractBackgroundThe National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) has established a centralized repository for human induced pluripotent stem cells (iPSCs) and fibroblasts in partnership with the National Institute on Aging (NIA). This is a critical resource for the research community, which can facilitate disease modeling, functional genetic studies, and drug development. However, the utility of this resource is still limited in terms of racial and ethnic diversity, which has the potential to bias neurodegenerative research and drug development unless steps are taken to create and share a more diverse array of cell lines.MethodAt NCRAD, banked iPSCs are subjected to quality control including short‐read whole genome sequencing (WGS). 78 samples have been submitted for sequencing; of these, data for 51 have been returned and analyzed, including multiple isogenic lines from three donors. WGS data was aligned, and quality control performed using Sentieon software, following GATK best practices. Data was combined with sequencing data from 2,548 1000 Genomes participants and pruned in PLINK. R package SNPRelate was used to generate a kinship matrix and perform principal component analysis (PCA). Clustering analysis was performed utilizing K‐means clustering to group samples into 5 clusters. PCs 1‐3 were graphed, color‐coded by cluster, and final ancestry calls reviewed for clustering with reference groups.ResultThe NCRAD 51 iPSC lines with analyzed WGS data were sourced from 28 neurodegenerative cases and 12 controls. In this data set, 83% of samples (89% of cases, 67% of controls) have European ancestry. The cohort also includes one case and one control line of East Asian ancestry, as well as 2 cases and 3 controls showing admixture of European/American ancestry. 17 individuals did not have reported race/ethnicity, while 2 controls showed genetic admixture though reported as White non‐Hispanic, and the remaining individuals’ genetic ancestry matched reported race/ethnicity.ConclusionCentralized banking of iPSCs from individuals with neurodegenerative diseases is creating a key resource to advance research; however, to date the diversity of these samples is limited. We urge researchers to develop and share more diverse cell lines, to promote diversity and equity in neurodegenerative research.

Assessing genetic diversity and defining signatures of positive selection on the genome of dromedary camels from the southeast of the Arabian Peninsula

Dromedary camels (Camelus dromedarius) are members of the Camelini tribe within the Camelidae family. They are distributed throughout North Africa, the Arabian Peninsula and Southeast Asia. This domestic species is characterized by its superior adaptability to the harsh desert environment. In this study, whole autosomal data of 29 dromedary samples from the Southeast Arabian Peninsula in Oman; 10 from Muscat, 14 from Al-Batinah, and 5 from Al-Sharqiya, were investigated to assess their genetic relationship and to define candidate signatures of positive selection. A minimal genetic distinction that separates Muscat dromedaries from the other two populations was observed, with a degree of genetic admixture between them. Using the de-correlated composite of multiple signals (DCMS) approach, a total of 47 candidate regions within the autosomes of these dromedary populations were defined with signatures of positive selection. These candidate regions harbor a total of 154 genes that are mainly associated with functional categories related to immune response, lipid metabolism and energy expenditure, optical and auditory functions, and long-term memory. Different functional genomic variants were called on the candidate regions and respective genes that warrant further investigation to find possible association with the different favorable phenotypes in dromedaries. The output of this study paves the way for further research efforts aimed at defining markers for use in genomic breeding programs, with the goal of conserving the genetic diversity of the species and enhancing its productivity.

Inferring multi-locus selection in admixed populations.

Admixture, the exchange of genetic information between distinct source populations, is thought to be a major source of adaptive genetic variation. Unlike mutation events, which periodically generate single alleles, admixture can introduce many selected alleles simultaneously. As such, the effects of linkage between selected alleles may be especially pronounced in admixed populations. However, existing tools for identifying selected mutations within admixed populations only account for selection at a single site, overlooking phenomena such as linkage among proximal selected alleles. Here, we develop and extensively validate a method for identifying and quantifying the individual effects of multiple linked selected sites on a chromosome in admixed populations. Our approach numerically calculates the expected local ancestry landscape in an admixed population for a given multi-locus selection model, and then maximizes the likelihood of the model. After applying this method to admixed populations of Drosophila melanogaster and Passer italiae, we found that the impacts between linked sites may be an important contributor to natural selection in admixed populations. Furthermore, for the situations we considered, the selection coefficients and number of selected sites are overestimated in analyses that do not consider the effects of linkage among selected sites. Our results imply that linkage among selected sites may be an important evolutionary force in admixed populations. This tool provides a powerful generalized method to investigate these crucial phenomena in diverse populations.

Large Deletion in the Factor VIII Gene Is a Predictor of Immune Tolerance Induction Failure in People with Severe and Moderately-Severe Hemophilia a and High-Responding Inhibitors

Introduction Immune tolerance induction (ITI) is a therapeutic approach to eradicate inhibitors against factor VIII (FVIII) in people with inherited hemophilia A (PwHA). The success of ITI is highly variable, ranging from 60% to 80% across studies. Beyond inhibitor titers, other predictors of ITI outcome are unknown. Deleterious variants in FVIII gene ( F8) are well established risk factors for alloantibodies development in PwHA, although few studies have investigated the role of F8 variants on ITI outcome.Therefore we aimed to comprehensively analyze the association of F8 pathogenic variants on ITI outcome in severe PwHA with high-responding inhibitors. Methods We included severe (FVIII < 1 international units [IU]/dL) and moderately-severe (FVIII 1-2 IU/dL) unrelated PwHA and high-responding inhibitors who completed ITI from a large, admixed population of two well-characterized cohorts - the HEMFIL and the Brazilian Immune Tolerance (BrazIT) studies. We collected socio-demographic, clinical and laboratory data. ITI outcomes were defined according to previous definitions as failure, partial and total successes. Inversions of intron 1 and 22 (Inv22) were detected by polymerase chain reaction (PCR), and high-throughput sequencing approaches were used to unveil the additional F8 variants. The association between F8 pathogenic variants and ITI outcome was adjusted for inhibitor levels. To investigate whether F8 variants associated with inhibitor development were also related to ITI outcome, variants were categorized as “high-risk”, “intermediate-risk”, and “low-risk” categories. These categories for inhibitor development were then compared with the outcomes of ITI (total and partial successes and failure) using data from this study. Results We included158 PwHA, median age 6.6 years at ITI start, 90.5% were severe (Table 1). Inv22 was the most prevalent variant (55.1%) (Table 1). In comparison with Inv22-1, the risk of ITI failure was about 9 times higher (adjusted odds ratio [adjOR] 9.29; 95% confidence interval [95% CI] 1.95-53.70) among carriers of large deletions (Table 2). Conversely, Inv22-2 was associated with favorable ITI outcome in a univariate analysis (OR 0.15; 0.01-0.84), and after adjustment (adjOR 0.32; 95% CI 0.02-1.96) (Table 2). F8 deleterious variants sorted as high-risk and intermediate-risk according to a previously published classification on inhibitor development were associated with failure and successful outcomes, respectively. Conclusion Our study showed that F8 large deletions are independent predictors of ITI failure, and Inv22-2 is likely to be a predictor of successful ITI. We found a correspondence between variants classified as high-risk and intermediate-risk to inhibitor development with ITI failure and success, respectively. We suggest that F8 genotyping should be considered before indication of ITI, as ITI outcome can vary according to individual variant burden.

Phylogenetic, population structure, and population demographic analyses reveal that Vicia sepium in Japan is native and not introduced

Vicia sepium (bush vetch) is a perennial legume widely distributed throughout the Eurasian continent. However, its distribution in Japan is limited to Mt. Ibuki and small parts of central and southern Hokkaido. Therefore, each Japanese V. sepium lineage has been considered to have been introduced separately from Europe. Here, we examined whether the species was introduced or not on the basis of cpDNA sequences and genome-wide SNPs from Japanese and overseas samples. Both the cpDNA haplotype network and the nuclear DNA phylogenetic tree showed that Japanese V. sepium is monophyletic. Furthermore, although the nuclear DNA phylogenetic tree also showed that each lineage is clearly monophyletic, genetic admixture of the genetic cluster dominated in the Hokkaido lineage was also detected in the Mt. Ibuki lineage. Population divergence analysis showed that the two lineages diverged during the last glacial period. The Mt. Ibuki lineage showed a sudden population decline 300–400 years ago, indicating that some anthropogenic activity might be involved, while the Hokkaido lineage showed a gradual population decline from 5000 years ago. Consequently, these two lineages show low current genetic diversity compared with overseas lineages. These results show that the Japanese V. sepium is not introduced but is native.

SNP genotyping revealed a hybrid zone between Mytilus chilensis and M. platensis in southern South America (the Strait of Magellan, Isla Grande de Tierra del Fuego and the Falkland Islands).

Hybrid zones among mussel species have been extensively studied in the northern hemisphere. In South America, it has only recently become possible to study the natural hybrid zones, due to the clarification of the taxonomy of native mussels of the Mytilus genus. Analysing 54 SNP markers, we show the genetic species composition and admixture in the hybrid zone between M. chilensis and M. platensis in the southern end of South America. Bayesian, non-Bayesian clustering and re-assignment algorithms showed that the natural hybrid zone between M. chilensis and M. platensis in the Strait of Magellan, Isla Grande de Tierra del Fuego and the Falkland Islands shows clinal architecture. The hybrid zone can be divided into three different areas: the first one is on the Atlantic coast where only pure M. platensis and hybrid were found. In the second one, inside the Strait of Magellan, pure individuals of both species and mussels with variable degrees of hybridisation coexist. In the last area at the Strait in front of Punta Arenas City, fjords on the Isla Grande de Tierra del Fuego, and at the Beagle Channel, only M. chilensis and a low number of hybrids were found. According to the proportion of hybrids, bays with protected conditions away from strong currents would give better conditions for hybridisation. We do not find evidence of any other mussel species such as M. edulis, M. galloprovincialis, M. planulatus or M. trossulus in the zone.

A benchmark study on current GWAS models in admixed populations.

The performances of popular genome-wide association study (GWAS) models have not been examined yet in a consistent manner under the scenario of genetic admixture, which introduces several challenging aspects: heterogeneity of minor allele frequency (MAF), wide spectrum of case-control ratio, varying effect sizes, etc. We generated a cohort of synthetic individuals (N = 19234) that simulates (i) a large sample size; (ii) two-way admixture (Native American and European ancestry) and (iii) a binary phenotype. We then benchmarked three popular GWAS tools [generalized linear mixed model associated test (GMMAT), scalable and accurate implementation of generalized mixed model (SAIGE) and Tractor] by computing inflation factors and power calculations under different MAFs, case-control ratios, sample sizes and varying ancestry proportions. We also employed a cohort of Peruvians (N = 249) to further examine the performances of the testing models on (i) real genetic and phenotype data and (ii) small sample sizes. In the synthetic cohort, SAIGE performed better than GMMAT and Tractor in terms of type-I error rate, especially under severe unbalanced case-control ratio. On the contrary, power analysis identified Tractor as the best method to pinpoint ancestry-specific causal variants but showed decreased power when the effect size displayed limited heterogeneity between ancestries. In the Peruvian cohort, only Tractor identified two suggestive loci (P-value $\le 1\ast{10}^{-5}$) associated with Native American ancestry. The current study illustrates best practice and limitations for available GWAS tools under the scenario of genetic admixture. Incorporating local ancestry in GWAS analyses boosts power, although careful consideration of complex scenarios (small sample sizes, imbalance case-control ratio, MAF heterogeneity) is needed.

The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease.

Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio =2.93 [2.37-3.63], P=2.6×10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.

Population genomics provides insights into the genetic diversity and adaptation of the Pieris rapae in China.

The cabbage white butterfly (Pieris rapae), a major agricultural pest, has become one of the most abundant and destructive butterflies in the world. It is widely distributed in a large variety of climates and terrains of China due to its strong adaptability. To gain insight into the population genetic characteristics of P. rapae in China, we resequenced the genome of 51 individuals from 19 areas throughout China. Using population genomics approaches, a dense variant map of P. rapae was observed, indicating a high level of polymorphism that could result in adaptation to a changing environment. The feature of the genetic structure suggested considerable genetic admixture in different geographical groups. Additionally, our analyses suggest that physical barriers may have played a more important role than geographic distance in driving genetic differentiation. Population history showed the effective population size of P. rapae was greatly affected by global temperature changes, with mild periods (i.e., temperatures warmer than those during glaciation but not excessively hot) leading to an increase in population size. Furthermore, by comparing populations from south and north China, we have identified selected genes related to sensing temperature, growth, neuromodulation and immune response, which may reveal the genetic basis of adaptation to different environments. Our study is the first to illustrate the genetic signatures of P. rapae in China at the population genomic level, providing fundamental knowledge of the genetic diversity and adaptation of P. rapae.

Characterization of the genetic diversity, structure, and admixture of 7 Chilean chicken breeds

The Mapuche fowl is an autochthonous breed raised in Chile and represents an important zoogenetic resource for the local economy. This study aimed at investigating the genetic diversity, relationship and population structure of 96 local Chilean chickens derived from 3 ecotype of Mapuche fowl (Kollonka, Ketro, and Kollonka de aretes), 2 ecotype Chilean (Trintre, Cogote pelado) and 2 breeds (Light Brahma and Barred Plymouth Rock) using 12 microsatellite markers. In total, 113 alleles were detected in all populations, with a mean of 7.6 alleles per population. In all population chicken breeds, the observed and expected heterozygosity ranged from 0.91 to 0.98 and from 0.69 to 0.79. Furthermore, all populations showed significant deviations from Hardy-Weinberg expectations. Across each population, the global heterozygosity deficit (FIT) was -0.174, population differentiation index (FST) was 0.073, and the global inbreeding of individuals within breed (FIS) was -0.267. The phylogenetic relationships of chickens were examined using neighbor-joining trees constructed at the level of population. The highest Nei's standard genetic distance value of 0.559 was observed between Barred Plymouth Rock and Light Brahma, whereas the minimum value (0.099) was found between Kollonka and Trintre. The neighbor-joining tree constructed at population level revealed 2 main clusters, with Light Brahma, Barred Plymouth Rock, Ketro and Kollonka de aretes in 1 cluster, and Kollonka, Trintre and Cogote pelado breeds in the second cluster. Based on the results of the STRUCTURE analysis, the most likely number of clustering of the population evaluated was at K=3, with Light Brahma and Barred Plymouth Rock breeds forming their own distinct clusters, while Kollonka, Ketro, Kollonka de aretes, Trintre and Cogote pelado breeds clustered together. This study represents the first report of genetic diversity in these populations in Chile. These results can be used as baseline genetic information for genetic conservation program, for instance, to control inbreeding and to implement further genetic studies in local Chilean chickens.