Pedigree Analysis Research Articles

Dense SNP-based analyses complement forensic anthropology biogeographical ancestry assessments

Identification of unidentified human remains (UHRs) is crucial yet challenging, especially with traditional forensic techniques. Forensic anthropological examinations can yield ancestry estimations; however, the utility of these estimates is limited by the data points that can be collected from partial remains, complexities of admixture, and variation of phenotypic expression due to environmental effects. While it is generally known that anthropological estimates can be imprecise, the performance of these methods has not been studied at scale. Genome-wide SNP testing is an orthogonal approach for estimating ancestry and offers a unique opportunity to measure the magnitude of anthropological ancestry misattribution. Genomic ancestry inference leverages principal component analysis (PCA) and model-based clustering approaches. This study compares anthropologically determined ancestry with those estimated using genome-wide SNP markers. A dataset of 611 UHR samples with publicly available ancestry assessments from National Missing and Unidentified Persons System (NamUs) was analyzed. The genetic ancestry approach, validated against reference population samples, offers robust ancestry calculations for major population groups. Inconsistency between anthropological and genomic ancestry assignments were observed, particularly for admixed populations. Although forensic anthropological examinations remain valuable, their limitations emphasize the need for refinement and enhancement through the augmentation of SNP-based analyses. Further validation studies are crucial to define the uncertainty associated with both anthropological and genome-based ancestry estimates to resolve cases and aid law enforcement investigations. Additionally, current policy and practices for reporting ancestry for UHRs should be revisited to reduce potential misinformation.

Genetic variation and molecular profiling of congenital malformations of the female genital tract based on whole-genome sequencing.

Congenital malformations of the female genital tract (CM-FGT) are characterized by abnormal development of the fallopian tubes, uterus, and vagina, often accompanied by malformations in the urinary system, bones and hearing. However, no definitive pathogenic genes and molecular genetic causes have been identified. We present the largest whole-genome sequencing study of CM-FGT to date, analyzing 590 individuals in China: 95 patients, 442 case-controls, and 53 familial controls. Among the patients, 5.3% carried known CM-FGT-related variants. Pedigree and case-control analyses in two dimensions of coding and non-coding regulatory regions revealed seven novel de novo copy number variations, 12 rare single-nucleotide variations, and 10 rare 3' untranslated region (UTR) mutations in genes related to CM-FGT, particularly highlighting ASH1L as a pathogenic gene. Single-cell sequencing data showed that the majority of CM-FGT-related risk genes are spatiotemporally specifically expressed early in uterus development. In conclusion, this study identified novel variants related to CM-FGT, particularly highlighting ASH1L as a pathogenic gene. The findings provide insights into the genetic variants underlying CM-FGT, with single-cell sequencing data revealing spatiotemporal specific expression patterns of key risk genes early in uterine development. This study significantly advances the understanding of CM-FGT etiology and genetic landscape, offering new opportunities for prenatal screening.

Low Genetic Impact of the Roman Occupation of Britain in Rural Communities.

The Roman period saw the empire expand across Europe and the Mediterranean, including much of what is today Great Britain. While there is written evidence of high mobility into and out of Britain for administrators, traders, and the military, the impact of imperialism on local, rural population structure, kinship, and mobility is invisible in the textual record. The extent of genetic change that occurred in Britain during the Roman military occupation remains underexplored. Here, using genome-wide data from 52 ancient individuals from eight sites in Cambridgeshire covering the period of Roman occupation, we show low levels of genetic ancestry differentiation between Romano-British sites and indications of larger populations than in the Bronze Age and Neolithic. We find no evidence of long-distance migration from elsewhere in the Empire, though we do find one case of possible temporary mobility within a family unit during the Late Romano-British period. We also show that the present-day patterns of genetic ancestry composition in Britain emerged after the Roman period.

Analysis of C-reactive protein omics-measures associates methylation risk score with sleep health and related health outcomes.

DNA methylation (DNAm) predictors of high sensitivity C-reactive protein (CRP) offer a stable and accurate means of assessing chronic inflammation, bypassing the CRP protein fluctuations secondary to acute illness. Poor sleep health is associated with elevated inflammation (including elevated blood CRP levels) which may explain associations of sleep insufficiency with metabolic, cardiovascular and neurological diseases. Our study aims to characterize the relationships among sleep health phenotypes and CRP markers -blood, genetic, and epigenetic indicators-within the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). In HCHS/SOL, methylation risk scores (MRS)-CRP and polygenetic risk score (PRS)-CRP were constructed separately as weighted sums of methylation beta values or allele counts, respectively, for each individual. Sleep health phenotypes were measured using self-reported questionnaires and objective measurements. Survey-weighted linear regression established the association between the multiple sleep phenotypes (obstructive sleep apnea (OSA), sleep duration, insomnia and excessive sleepiness symptom), cognitive assessments, diabetes and hypertension with CRP markers while adjusting for age, sex, BMI, study center, and the first five principal components of genetic ancestry in HCHS/SOL. We included 2221 HCHS/SOL participants (age range 37-76 yrs, 65.7% female) in the analysis. Both the MRS-CRP (95% confidence interval (CI): 0.32-0.42, p = 3.3 × 10-38) and the PRS-CRP (95% CI: 0.15-0.25, p = 1 × 10-14) were associated with blood CRP level. Moreover, MRS-CRP was associated with sleep health phenotypes (OSA, long sleep duration) and related conditions (diabetes and hypertension), while PRS-CRP markers were not associated with these traits. Circulating CRP level was associated with sleep duration and diabetes. Associations between OSA traits and metabolic comorbidities weakened after adjusting for MRS-CRP, most strongly for diabetes, and least for hypertension. MRS-CRP is a promising estimate for systemic and chronic inflammation as reflected by circulating CRP levels, which either mediates or serves as a common cause of the association between sleep phenotypes and related comorbidities, especially in the presence of diabetes.

Individual Identification and Assessment of Genetic Diversity Using Microsatellite Markers in Racing Pigeons Raised in Turkiye

The implementation of a swift and economical molecular genetic approach, ensuring both efficacy and cost-effectiveness and facilitating population certification, is of utmost significance for breeders and the conservation of Turkiye's native pigeon biodiversity. In this study, we aimed to examine the genetic structure of racing pigeons (Columba livia domestica) raised in Turkiye using a genetic marker panel consisting of eight short tandem repeat (STR) loci. For this purpose, DNA was isolated from the shed feathers of 216 pigeons. Genomic DNA was amplified using the multiplex allele-specific PCR and subsequent capillary electrophoresis with ABI PRISM 3130XL Genetic Analyzer. Next, PCR products were analyzed in the GeneMapper Software program (Applied Biosystems). For parent testing, paternity index (PI), combined paternity index (CPI), and cumulative probability of paternity (CPP) were calculated. Furthermore, population genetic diversity was evaluated using heterozygosity (He), polymorphism information content (PIC), and Hardy–Weinberg equilibrium (HWE) testing. Results revealed that the total number of alleles is 81 and the number of alleles per locus varies between 4 and 19. The similarity rate between parent and offspring was calculated as 99.99% and above. Since no pedigree information was given when the samples were analyzed, obtaining this similarity ratio demonstrates the reliability of the panel. He values range from 0.362 to 0.919, and the PIC values range from 0.295 to 0.909. Loci PG-1, PG-2, and PG-3 show significant genetic diversity, with moderate to high PIC values reflecting varied allele frequencies in the population. Consequently, the set of seven STR markers (+ one sex marker) can be applied to identify and confirm parentage on a regular basis, thereby facilitating efficient breeding programs and ensuring genetic diversity conservation. This panel enables efficient pedigree analysis and gender determination, optimizing cost-effectiveness. The methodology presented in this study is ideal for pedigree analysis and breed certification in the Turkish pigeon breeding industry. Consequently, we affirm that the study data carries considerable national importance.

Genetic analysis of asymptomatic antinuclear antibody production.

Antinuclear antibodies (ANA) are detected in up to 14% of the population and the majority of individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity in the population is limited. In this study, we aimed to perform a multi-ancestry genome-wide association study (GWAS) of asymptomatic ANA positivity. Asymptomatic ANA positive and negative individuals from the All of Us Research Program were included in this study, selecting those with an ANA test by immunofluorescence and no evidence of autoimmune disease. Imputation was performed and a multi-ancestry meta-analysis including approximately 6 million single-nucleotide polymorphisms (SNPs) was conducted. Genome-wide SNP based heritability was estimated using the GCTA software. A cumulative genetic risk score for lupus was constructed using previously reported genome-wide significant loci. 1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals were included across three genetic ancestries. The multi-ancestry meta-analysis revealed SNPs with a suggestive association (p-value < 1×10 -5 ) across 8 different loci, but no genome-wide significant loci were identified. A gene variant upstream of HLA-DQB1 (rs17211748, P = 1.4×10 -6 , OR = 0.82, 95% CI 0.76-0.89) showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Asymptomatic ANA positive individuals did not exhibit increased cumulative genetic risk for lupus compared to ANA negative individuals. ANA production is not associated with significant genetic risk and is primarily determined by non-genetic, likely environmental, factors.

Ancestral influences: multiple sclerosis, ethnicity and equity in genetic research

Multiple sclerosis is not an inherited disease, but those who have family members with the disease have a higher risk of developing it themselves. The disease's impacts can vary depending on genetic ancestry. Much of the existing research on MS uses data from European populations. This article provides insight into wider international research that aims to rebalance health outcomes between people of non-White European backgrounds.

First Molecular Diagnosis of Oestrus ovis (Linnaeus, 1758) Larvae Causing Conjunctival Ophthalmomyiasis in Mexico City, Mexico.

Human ophthalmomyiasis is a rare ocular parasitosis that results from the accidental infestation of dipteran larvae of several species, including Oestrus ovis (Linnaeus, 1758). This study aims to present the fourth documented human case of ophthalmomyiasis in Mexico, identifying the etiological agent through morphological and molecular analyses. Additionally, we investigated the phylogenetic position and genetic distances among different specimens globally characterized based on mitochondrial Cox1 sequences. A total of five larval specimens were extracted from the patient's eye, with two specimens allocated for identification based on morphological features using a stereomicroscope, and the remaining three preserved in absolute ethanol, one of them used for subsequent analysis using molecular methods. The mitochondrial Cox1 region was amplified and sequenced using automated Sanger sequencing. The resulting sequence was deposited in GenBank under accession number OR440699 and subjected to BlastN analysis against 35 other Cox1 sequences of O. ovis from GenBank. The identity and phylogenetic position of the strains were further explored using parsimony and maximum likelihood phylogenetic methods. Morphological examination of the larval specimens extracted from the patient's eye unequivocally identified them as O. ovis species. BlastN analysis and comprehensive phylogenetic investigations involving a total of 36 Cox1 sequences confirmed the taxonomic identity of the larvae. Notably, our sequence was positioned within the cluster formed by the Brazilian and two Iranian samples. This finding underscores a shared genetic ancestry among these distinct geographical isolates and provides valuable insights into the evolutionary relationships within O. ovis populations. The presence of O. ovis infestation in Mexico City suggests potential shifts in environmental conditions favoring fly proliferation, highlighting the need for vigilance in urban healthcare settings.

Phenotypic Heterogeneity of Patients With Marfan Syndrome in Puerto Rico: A Case Series.

Previous studies have reported on the cardiovascular, ocular, and musculoskeletal findings in patients with Marfan syndrome (MFS). This study aims to report the ocular and genotypic findings in patients with the syndrome in Puerto Rico. A chart review of a cohort of patients with the syndrome from Puerto Rico was done. Patients were examined by at least one of the authors (NJI). Fibrillin-1 (FBN1) full gene sequencing was done to all patients (Laboratory for Molecular Medicine, Center for Genetics and Genomics, Cambridge, MA). This study was approved by the Institutional Review Board of the Universidad Central del Caribe (approval number: 2024-07). Results: Six patients aged 28-79 years were examined. There were seven female and three male patients. The average visual acuity was 0.49 and 0.52 in the right eye (OD) and left eye (OS), respectively. The average refraction (spherical equivalent) was -1.28 sph OD and -1.07 sph OS. The average intraocular pressure was 14 mmHg in both eyes (OU). A patient had a dislocated lens OD; a patient had lens dislocation OU; and a patient had prosthesis OD and aphakia OS. Upon optical coherence tomography (OCT), the retinal nerve fiber layer (RNFL) average was 75.86 µm OD and 81.85 ​​µm OS; the average cup-to-disc (C/D) ratio was 0.41 and 0.35 in the right and left eye, respectively. Upon visual field testing, the average mean deviation (MD) was -6.27 dB OD and -8.55 dB OS. Our findings underscore the significant phenotypic and genotypic heterogeneity of patients with MFS in Puerto Rico. The identification of several mutations in the FBN1 gene in the Puerto Rican population demonstrates the need for an up-to-date approach to diagnose and co-manage patients with the syndrome. This study contributes to a deeper understanding of the genetic heritage of patients with the syndrome and highlights the potential for personalized therapeutic interventions.

Genetic ancestry proportion influences risk of adverse events from tuberculosis treatment in Brazil.

Tuberculosis (TB) treatment is highly effective, but response to therapy can vary by geography, race, and ethnicity. We assessed for differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry proportion according to major ancestry groups (African, European, and Amerindian ancestry) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. TB treatment outcomes that were attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Ancestry proportion was the main predictor in logistic regression for each outcome, with adjustments for candidate confounders. There were 941 pulmonary TB patients included in this study. We observed a decreased risk of Grade 2+ ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20 -0.85) and an increased risk for Grade 2+ ADR with increasing European ancestry (OR 2.84, 95% CI 1.47 - 5.48). We then performed the same analysis adding HIV status as an interaction term. The decreased risk for Grade 2+ ADR seen for African ancestry proportion did not hold for persons living with HIV; we observed increased risk for Grade 2+ ADR with increasing African ancestry proportion. There were no associations with Amerindian ancestry or for other treatment outcomes. In this Brazilian TB cohort, toxicity risk was associated with African and European ancestry, divergent, and affected by HIV. #RePORT-Brazil Consortium members include: Aline Benjamin and Flavia M. Sant'Anna Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil Jamile Garcia de Oliveira and João Marine Clínica de Saúde Rinaldo Delmare, Rio de Janeiro, Brazil Adriana Rezende and Anna Cristina Carvalho Secretaria de Saúde de Duque de Caxias, Rio de Janeiro, Brazil Michael Rocha and Betânia Nogueira Instituto Brasileiro para Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil Alexandra Brito and Renata Spener Fundação Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil Megan Turner Vanderbilt University Medical Center, Nashville, USA.

Rare coding variant analysis for human diseases across biobanks and ancestries.

Large-scale sequencing has enabled unparalleled opportunities to investigate the role of rare coding variation in human phenotypic variability. Here, we present a pan-ancestry analysis of sequencing data from three large biobanks, including the All of Us research program. Using mixed-effects models, we performed gene-based rare variant testing for 601 diseases across 748,879 individuals, including 155,236 with ancestry dissimilar to European. We identified 363 significant associations, which highlighted core genes for the human disease phenome and identified potential novel associations, including UBR3 for cardiometabolic disease and YLPM1 for psychiatric disease. Pan-ancestry burden testing represented an inclusive and useful approach for discovery in diverse datasets, although we also highlight the importance of ancestry-specific sensitivity analyses in this setting. Finally, we found that effect sizes for rare protein-disrupting variants were concordant between samples similar to European ancestry and other genetic ancestries (βDeming = 0.7-1.0). Our results have implications for multi-ancestry and cross-biobank approaches in sequencing association studies for human disease.

Characterizing features affecting local ancestry inference performance in admixed populations.

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using Local Ancestry Inference (LAI). Accurate LAI is crucial to ensure downstream analyses reflect the genetic ancestry of research participants accurately. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries - African (AFR), Amerindigenous (AMR), and European (EUR). Simulating LD-informed admixed haplotypes under a variety of 2 and 3-way admixture models, we implemented a standard LAI pipeline, testing three reference panel compositions to quantify their overall and ancestry-specific accuracy. We examined LAI miscall frequencies and true positive rates (TPR) across simulation models and continental ancestries. AMR tracts have notably reduced LAI accuracy as compared to EUR and AFR tracts in all comparisons, with TPR means for AMR ranging from 88-94%, EUR from 96-99% and AFR 98-99%. When LAI miscalls occurred, they most frequently erroneously called European ancestry in true Amerindigenous sites. Using a reference panel well-matched to the target population, even with a lower sample size, LAI produced true-positive estimates that were not statistically different from a high sample size but mismatched reference, while being more computationally efficient. While directly responsive to admixed Latin American cohort compositions, these trends are broadly useful for informing best practices for LAI across other admixed populations. Our findings reinforce the need for inclusion of more underrepresented populations in sequencing efforts to improve reference panels.

It’s all relative: A multi-generational study using ForenSeq™ Kintelligence

The successful application of Forensic Investigative Genetic Genealogy (FIGG) to the identification of unidentified human remains and perpetrators of serious crime has led to a growing interest in its use internationally, including Australia. Routinely, FIGG has relied on the generation of high-density single nucleotide polymorphism (SNP) profiles from forensic samples using whole genome array (WGA) (∼650,000 or more SNPs) or whole genome sequencing (WGS) (millions of SNPs) for DNA segment-based comparisons in commercially available genealogy databases. To date, this approach has required DNA of a quality and quantity that is often not compatible with forensic samples. Furthermore, it requires the management of large data sets that include SNPs of medical relevance. The ForenSeq™ Kintelligence kit, comprising of 10,230 SNPs including 9867 for kinship association, was designed to overcome these challenges using a targeted amplicon sequencing-based method developed for low DNA inputs, inhibited and/or degraded forensic samples. To assess the ability of the ForenSeq™ Kintelligence workflow to correctly predict biological relationships, a comparative study comprising of 12 individuals from a family (with varying degrees of relatedness from 1st to 6th degree relatives) was undertaken using ForenSeq™ Kintelligence and a WGA approach using the Illumina Global Screening Array-24 version 3.0 Beadchip. All expected 1st, 2nd, 3rd, 4th and 5th degree relationships were correctly predicted using ForenSeq™ Kintelligence, while the expected 6th degree relationships were not detected. Given the (often) limited availability of forensic samples, findings from this study will assist Australian Law enforcement and other agencies considering the use of FIGG, to determine if the ForenSeq™ Kintelligence is suitable for existing workflows and casework sample types considered for FIGG.

AGT, CYP11B2 & ADRB2 gene polymorphism & essential hypertension (HT): A meta-analysis.

Background & objectives The results of the genetic association studies between the selected candidate genes and hypertension (HT) contradicted across different populations. Majority of the meta-analyses carried out did not consider population genetic ancestry as a confounding factor. Therefore, this meta-analysis attempted to consolidate and re-evaluate the findings of the association between the selected candidate variants (AGT-rs699, CYP11B2-rs1799998, ADRB2-rs1042713 and rs1042714) and HT, by categorizing the genotyping data based on known genetic ancestry, and/or major geographical populations. Methods Publications were retrieved from PubMed, Cochrane and World of Science. The included articles were further divided into different populations based on their known genetic and/or geographical ancestry. Results AGTrs699-G was significantly associated with HT among Indians for (i) allele [P=0.03, Odds ratio (OR): 1.37, 95% Confidence Interval (CI): 1.03-1.82], and (ii) dominant mode of inheritance (P=0.009, OR:1.45, 95% CI: 1.09-1.91). CYP11B2rs1799998-G was significantly associated with HT in Europeans for (i) allele (P=6.9 × 10-5, OR: 0.82, 95% CI: 0.74-0.9), (ii) recessive (P=6.38 × 10-5, OR: 0.7, 95% CI: 0.59-0.83) and (iii) dominant mode of inheritance (P=0.008, OR: 0.81, 95% CI: 0.7-0.94). ADRB2-rs1042713-G was significantly associated with HT in east Asians for (i) allele (P=0.01, OR: 1.26, 95% CI: 1.05-1.51), and (ii) recessive mode of inheritance (P=0.04, OR: 1.36, 95% CI: 1.01-1.83). Interpretation & conclusions Different genotype and allele frequencies in diverse populations result in different genetic associations with HT across populations. This meta-analysis finding provides an update and summary of the genetic association between the selected simple nucleotide polymorphism (SNPs) and HT across different populations and essential insights into selecting appropriate pharmacogenetic marker(s) for effective HT management in populations of different ancestries.

Improving genetic risk modeling of dementia from real-world data in underrepresented populations

Genetic risk modeling for dementia offers significant benefits, but studies based on real-world data, particularly for underrepresented populations, are limited. We employ an Elastic Net model for dementia risk prediction using single-nucleotide polymorphisms prioritized by functional genomic data from multiple neurodegenerative disease genome-wide association studies. We compare this model with APOE and polygenic risk score models across genetic ancestry groups (Hispanic Latino American sample: 610 patients with 126 cases; African American sample: 440 patients with 84 cases; East Asian American sample: 673 patients with 75 cases), using electronic health records from UCLA Health for discovery and the All of Us cohort for validation. Our model significantly outperforms other models across multiple ancestries, improving the area-under-precision-recall curve by 31–84% (Wilcoxon signed-rank test p-value <0.05) and the area-under-the-receiver-operating characteristic by 11–17% (DeLong test p-value <0.05) compared to the APOE and the polygenic risk score models. We identify shared and ancestry-specific risk genes and biological pathways, reinforcing and adding to existing knowledge. Our study highlights the benefits of integrating functional mapping, multiple neurodegenerative diseases, and machine learning for genetic risk models in diverse populations. Our findings hold potential for refining precision medicine strategies in dementia diagnosis.

BaTwa populations from Zambia retain ancestry of past hunter-gatherer groups

Sub-equatorial Africa is today inhabited predominantly by Bantu-speaking groups of Western African descent who brought agriculture to the Luangwa valley in eastern Zambia ~2000 years ago. Before their arrival the area was inhabited by hunter-gatherers, who in many cases were subsequently replaced, displaced or assimilated. In Zambia, we know little about the genetic affinities of these hunter-gatherers. We examine ancestry of two isolated communities in Zambia, known as BaTwa and possible descendants of recent hunter-gatherers. We genotype over two million genome-wide SNPs from two BaTwa populations (total of 80 individuals) and from three comparative farming populations to: (i) determine if the BaTwa carry genetic links to past hunter-gatherer-groups, and (ii) characterise the genetic affinities of past Zambian hunter-gatherer-groups. The BaTwa populations do harbour a hunter-gatherer-like genetic ancestry and Western African ancestry. The hunter-gatherer component is a unique local signature, intermediate between current-day Khoe-San ancestry from southern Africa and central African rainforest hunter-gatherer ancestry.

Genomic characterisation and diversity assessment of eight endangered Belgian sheep breeds

Assessing the genetic diversity of local breeds is essential for conserving these unique breeds, which may possess unique traits. This study provides the genomic characterisation of eight indigenous sheep breeds in Belgium based on pedigree and single nucleotide polymorphism (SNP) analysis. A total of 687 sheep were genotyped and were subjected to a rigorous quality control, resulting in a set of 45 978 autosomal SNPs. Pedigree analysis showed breed-average inbreeding estimates between 3.3% and 11.3%. The genomic analysis included an assessment of runs of homozygosity (ROH) to examine the genomic inbreeding coefficient, with breed-average inbreeding coefficients estimated between 4.1% and 8.5%. Runs of homozygosity islands were identified in six of the eight breeds studied, with some exhibiting an incidence of up to 58%. Interestingly, several ROH islands overlapped with other breeds included in this study, as well as with international sheep breeds. Pedigree-based effective population sizes were estimated below 100 for all breeds, whereas genomic-based effective population sizes were below 24, indicating that these eight local sheep breeds are endangered. Principal component analysis, admixture analyses, and Fst computations were used to study the population structure and genetic differences. A neighbour−joining tree using 95 international sheep breeds positioned the eight local breeds in the group of milksheep, Texel sheep and the Scandinavian breeds. Additionally, the investigation of paternal oY1 genotypes revealed diverse lineage origins within the Belgian sheep population. This study refines and deepens our knowledge about the local sheep breeds in Belgium, thereby improving their management and conservation. Moreover, as these breeds are linked to other international breeds, these insights are significant for the global scientific community.

Metabolomic Profile Alterations Associated with the SLC16A11 Risk Haplotype Following a Lifestyle Intervention in People With Prediabetes

BackgroundA risk haplotype in SLC16A11 characterized by alterations in fatty acid metabolism emerged as a genetic risk factor associated with increased susceptibility to type 2 diabetes (T2D) in Mexican population. Its role on treatment responses is not well understood. ObjectivesWe aimed to determine the impact of the risk haplotype on the metabolomic profile during a lifestyle intervention (LSI). MethodsWe recruited Mexican-mestizo individuals with ≥1 prediabetes criteria according to the American Diabetes Association with a body mass index between 25 and 45 kg/m2. We conducted a 24-wk quasiexperimental LSI study for diabetes prevention. Here, we compared longitudinal plasma liquid chromatography/mass spectrometry metabolomic changes between carriers and noncarriers. We analyzed the association of risk haplotype with metabolites leveraging repeated assessments using multivariable-adjusted linear mixed models. ResultsBefore the intervention, carriers (N = 21) showed higher concentrations of hippurate, C16 carnitine, glycine, and cinnamoylglycine. After 24 wk of LSI, carriers exhibited a deleterious metabolomic profile. This profile was characterized by increased concentrations of hippurate, cinnamoglycine, xanthosine, N-acetylputrescine, L-acetylcarnitine, ceramide (d18:1/24:1), and decreased concentrations of citrulline and phosphatidylethanolamine. These metabolites were associated with higher concentrations of total cholesterol, triglycerides, and low density lipoprotein cholesterol. The effect of LSI on the risk haplotype was notably more pronounced in its impact on 2 metabolites: methylmalonylcarnitine (β: −0.56; P-interaction = 0.014) and betaine (β: −0.64; P-interaction = 0.017). Interestingly, lower consumption across visits of polyunsaturated (β: −0.038; P = 0.017) fatty acids were associated with higher concentrations of methylmalonylcarnitine. Covariates for adjustment across models included age, sex, genetic ancestry principal components, and body mass index. ConclusionsOur study highlights the persistence of deleterious metabolomic patterns associated with the risk haplotype before and during a 24-wk LSI. We also emphasize the potential regulatory role of polyunsaturated fatty acids on methylmalonylcarnitine concentrations suggesting a route for improving interventions for individuals with high-genetic risk.

Three Open Questions in Polygenic Score Portability.

A major obstacle hindering the broad adoption of polygenic scores (PGS) is their lack of "portability" to people that differ-in genetic ancestry or other characteristics-from the GWAS samples in which genetic effects were estimated. Here, we use the UK Biobank to measure the change in PGS prediction accuracy as a continuous function of individuals' genome-wide genetic dissimilarity to the GWAS sample ("genetic distance"). Our results highlight three gaps in our understanding of PGS portability. First, prediction accuracy is extremely noisy at the individual level and not well predicted by genetic distance. In fact, variance in prediction accuracy is explained comparably well by socioeconomic measures. Second, trends of portability vary across traits. For several immunity-related traits, prediction accuracy drops near zero quickly even at intermediate levels of genetic distance. This quick drop may reflect GWAS associations being more ancestry-specific in immunity-related traits than in other traits. Third, we show that even qualitative trends of portability can depend on the measure of prediction accuracy used. For instance, for white blood cell count, a measure of prediction accuracy at the individual level (reduction in mean squared error) increases with genetic distance. Together, our results show that portability cannot be understood through global ancestry groupings alone. There are other, understudied factors influencing portability, such as the specifics of the evolution of the trait and its genetic architecture, social context, and the construction of the polygenic score. Addressing these gaps can aid in the development and application of PGS and inform more equitable genomic research.

Local Ancestry Inference Based on Population-Specific Single-Nucleotide Polymorphisms-A Study of Admixed Populations in the 1000 Genomes Project.

Human populations have interacted throughout history, and a considerable portion of modern human populations show evidence of admixture. Local ancestry inference (LAI) is focused on detecting the genetic ancestry of chromosomal segments in admixed individuals and has wide applications. In this work, we proposed a new LAI method based on population-specific single-nucleotide polymorphisms (SNPs) and applied it in the analysis of admixed populations in the 1000 Genomes Project (1KGP). Based on population-specific SNPs in a sliding window, we computed local ancestry information vectors, which are moment estimators of local ancestral proportions, for two haplotypes of an admixed individual and inferred the local ancestral origins. Then we used African (AFR), East Asian (EAS), European (EUR) and South Asian (SAS) populations from the 1KGP and indigenous American (AMR) populations from the Human Genome Diversity Project (HGDP) as reference populations and conducted the proposed LAI analysis on African American populations and American populations in the 1KGP. The results were compared with those obtained by RFMix, G-Nomix and FLARE. We demonstrated that the existence of alleles in a chromosomal region that are specific to a particular reference population and the absence of alleles specific to the other reference populations provide reasonable evidence for determining the ancestral origin of the region. Contemporary AFR, AMR and EUR populations approximate ancestral populations of the admixed populations well, and the results from RFMix, G-Nomix and FLARE largely agree with those from the Ancestral Spectrum Analyzer (ASA), in which the proposed method was implemented. When admixtures are ancient and contemporary reference populations do not satisfactorily approximate ancestral populations, the performances of RFMix, G-Nomix and FLARE deteriorate with increased error rates and fragmented chromosomal segments. In contrast, our method provides fair results.