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Results for “admixture mapping”

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PubMed2025

Admixture-mapping analysis reveals genetic determinants of the human plasma proteome.

Protein profiling and genetic findings can be integrated to define the genetic architecture of the circulating proteome in chronic diseases. Most self-identified African American (AA) individuals have both African and European genetic ancestry. Admixture mapping can detect genomic association regions in which causal variants exist with substantial differences in allele frequency or effect sizes between genetic ancestries. We performed admixture mapping of the circulating proteome in 1,989 participants from the Jackson Heart Study (JHS), investigating the relation of local African ancestry within genomic regions with levels of circulating proteins. We conditioned protein-local ancestry association models on variants previously found to be associated with those proteins in genome-wide association studies (GWASs). We replicated findings in 196 AA participants from the Multi-Ethnic Study of Atherosclerosis (MESA). 62 proteins were associated with local African ancestry. 21 of 62 remained statistically significant after conditioning on protein-associated variants observed in previous GWASs. 48 of 54 available protein-local ancestry associations were replicated in the MESA. Proteins associated with local African ancestry included chemokines, factors associated with vascular biology and inflammation, and other biologically interesting proteins. Admixture associations unexplained by previously reported protein-associated variants in conditional analysis suggest the existence of causal variants missed by standard GWAS techniques.

Aged↗

PubMed2025

Admixture Mapping Reveals Evidence for Multiple Mitonuclear Incompatibilities in Swordtail Fish Hybrids.

How barriers to gene flow arise between closely related species is one of the oldest questions in evolutionary biology. Classic models in evolutionary biology predict that negative epistatic interactions between variants in the genomes of diverged lineages, known as hybrid incompatibilities, will reduce viability or fertility in hybrids. The genetic architecture of these interactions and the evolutionary paths through which they arise have profound implications for the efficacy of hybrid incompatibilities as barriers to gene flow between species. While these questions have been studied using theoretical approaches for several decades, only recently has it become possible to genetically map larger numbers of hybrid incompatibilities. Here, we use admixture mapping in natural hybrid populations of swordtail fish (Xiphophorus) to identify hybrid incompatibilities involving genetic interactions between the mitochondrial and nuclear genomes. We find that at least nine regions of the genome are involved in mitonuclear incompatibilities. These incompatibilities involve interactions between the nuclear genome and the X. malinche mitochondria, the X. birchmanni mitochondria, or both. Moreover, they vary in the strength of selection they experience and the degree to which they limit gene flow in natural hybrid populations. Our results build a deeper understanding of the complex architecture of selection against incompatibilities in naturally hybridising species and highlight an important role of mitonuclear interactions in the evolution of reproductive barriers between closely related species.

Animals↗

PubMed2026

Large-scale admixture mapping in the All of Us Research Program improves the characterization of cross-population phenotypic differences.

Admixed individuals have been understudied in medical research largely due to their complex genetic ancestries. However, the consideration of admixture can identify ancestry-enriched genetic associations, delineating genetic underpinnings of cross-population phenotypic variation. Here, we performed admixture mapping in individuals with inferred admixture from African and European populations (N = 48,921). Across 22 traits, we identified 71 ancestry-trait associations, including loci where ancestral haplotypes explained phenotypic variation yet were missed by single-variant association testing due to their stricter multiple testing burden. One such locus where inferred local AFR ancestries are associated with increased hemoglobin A1c (HbA1c) was 12q14.3, highlighting its potential role in explaining differences between populations. Together, our results expand upon the phenotypic differences between populations and characterize loci where genetic ancestries play a critical role in the architecture of disease.

Humans↗

PubMed2025

Large-scale admixture mapping in the All of Us Research Program improves the characterization of cross-population phenotypic differences.

Admixed individuals have largely been understudied in medical research due to their complex genetic ancestries. However, the consideration of admixture can help identify ancestry-enriched genetic associations, delineating some of the genetic underpinnings of cross-population phenotypic variation. To this end, we performed local ancestry inference within the All of Us Research Program to identify individuals with recent admixture between African (AFR) and European (EUR) populations (N=48,921). We identified evidence of local AFR ancestry enrichment at the HLA locus, suggestive of putative selection since admixture. Furthermore, we performed the largest admixture mapping (ADM) efforts in AFR-EUR Admixed individuals for 22 traits, identifying 71 associations between inferred local AFR ancestries and a trait. Variants from published GWAS could only account for 18 (25%) of the ADM associations, highlighting novel loci where ancestral haplotypes explained some phenotypic variation. Previous studies likely have not identified these loci due to the low availability of high-powered GWAS in populations genetically similar to AFR. One such loci was 9q21.33, associated with 1.4-fold risk of end-stage kidney disease (ESKD) for carriers of inferred local AFR ancestries at the region. This locus contains the gene SLC28A3, which has previously been linked to kidney function but has never been associated with cross-population ESKD prevalence differences. Together, our results expand upon the existing literature on phenotypic differences between populations, highlighting loci where genetic ancestries play a critical role in the genetic architecture of disease.

Journal Article↗

PubMed2026

Characterizing features of the genetic architecture underlying autism from a multi-ancestry perspective.

Autism spectrum disorder (ASD; MIM 209850) is reported to vary globally from 0.01% in East Asian populations to 4.36% in certain Australian cohorts. Despite high heritability estimates (61-94%), the genetic architecture underlying ASD susceptibility remains poorly characterized across diverse populations, as most genomic studies have initially focused on individuals of European ancestry. To investigate ancestry-specific genetic contributions to ASD, we analyzed whole-genome sequencing data from three independent ASD cohorts. We identified admixed ASD probands (n = 1 033) and ancestry-matched controls (n = 1 033) and performed admixture mapping (AM). AM using five continental reference populations (European, African, East Asian, South Asian, and Native American) identified five ancestry-specific ASD-susceptibility loci, including one African-related locus at 1p21.2 near S1PR1 and four Native American-associated loci at chromosome 11q13.4. Three of these latter loci were contiguous and encompassed genes previously implicated in ASD, notably SHANK2 and DHCR7, with fine-mapping identifying a significantly associated variant between the two genes (rs77695321; P = 1.52 × 10⁻⁷). The fourth Native American-associated signal at 11q13.4 overlapped the folate receptor genes FOLR1 and FOLR3, with fine-mapping identifying a genome-wide significant variant (rs7950807; P = 5.21 × 10⁻⁸). A secondary admixture mapping analysis restricted to Latin American individuals, incorporating 6 487 Brazilian controls, identified 16 additional ancestry-specific loci across seven genomic regions.

Journal Article↗

PubMed1975

The role of macrophages in the generation of T-helper cells. II. The genetic control of the macrophage-T-cell interaction for helper cell induction with soluble antigens.

Helper cell induction to nonparticle antigens in vitro requires the cooperation of T cells and macrophages, but does not occur if the macrophages are allogenic. The reasons for this were investigated. Malfunction of allogenic macrophages was excluded by cultures with their syngenic T cells; suppressor cell induction was excluded by admixture experiments. Thus, T cells and macrophages only cooperated if they were genetically similar. The genetic locus (loci) involved was mapped. Using congenic lines differing only at the H-2 complex, the genetic control of T-macrophage interaction was localized in the H-2 region. Mice with intra H-2 recombinants were used to map the T-macrophage interaction locus in the I-A region of the H-2 complex (formerly known as poly-D, L-ala-poly-L-lys. Recombinants were also used to exclude the presence of another T-macrophage locus either the K, I-B, or I-C, SS-Slp, or D regions of the H-2 complex. Genetic restrictions for T-macrophage interaction in helper cell induction was shown in mice of the H-2-k, d, b, q, s genotypes as well as in H-2 recombinants. The possible mechanisms and significance of this genetic restriction are discussed.

Amino Acids↗

PubMed1976

Topographic studies on medial reticular nucleus.

Several distinct classes of neurons have been identified in the medial reticular nucleus of the medulla and pons and in proximity thereto. Neurons projecting down the spinal cord comprised the principal class with two subclasses according as the neurons did or did not receive monosynaptic inputs from the fastigial nuclei of the cerebellum. Two other classes were recognized accordings as they projected to the cerebellum or rostrally to the mesencephalon. Topographic planar maps giving the location of these neurons have been constructed by exploring the nucleus with series of microelectrode tracks in parasagittal or in transverse planes. The different classes of neurons were not arranged in large discrete nuclei. In part they appeared to be randomly distributed, but many colonies of one or another class of neurons could be recognized with 3-11 neurons in zones with dimensions of a millimeter or so. Because of the limitations of sampling by microelectrode tracks at spacings of 0.5 mm, single colonies might have an actual population of 100 or more. Many of the class of neurons projecting to the cerebellum were in the region of the perihypoglossal nucleus. However, almost as many were located deep in the medial reticular nucleus. None was found at the pontine level. Reticulospinal neurons with fast axonal conduction velocities tended to be located dorsally to those with slow velocities. Correlation with the findings of Ito et al. leads to the conjecture that the neurons with fast axons are excitatory, while those with slow axons are primary inhibitory neurons. There is a brief reference to the problems raised by the admixture of the various neuronal classes, there being discrete colonies immersed in a scattered arrangement of all classes.

Animals↗

PubMed1975

Somatotopic studies on red nucleus: spinal projection level and respective receptive fields.

The somatotopic inputs into red nucleus (RN) neurons have been studied with special reference to their level of projection in the spinal cord. As inputs we employed either volleys in predominantly cutaneous nerves of forelimb and hindlimb or cutaneous mechanoreceptor discharges evoked by taps to footpads of forelimb and hindlimb. There has been physiological confirmation of the anatomical findings that RD neurons projecting to the lumbar cord are located in the ventrolateral zone of the pars magnocellularis, whereas in the dorsomedial zone are RN neurons with cervical but not lumbar projection. Somatotopically there was found to be a differentiation of input to RN neurons according as they projected to the lumbar or only to the cervical cord. This finding was presented in the form both of tables and of somatotopic maps. As expected, this discrimination was more restrictive for the more selective inputs from pad taps than for nerve inputs. Nevertheless, forelimb inputs often had a considerable excitatory and inhibitory action on lumbar-projecting RN neurons, and vice versa for cervical-projecting neurons. There were two notable somatotopic findings that suggest specificities of connectivities. First, despite the large convergence of IP neurons onto RN neurons (about 50-fold), the degree of somatotopic discrimination was about the same for interpositus and RN neurons with two testing procedures: between inputs from forelimb and hindlimb; and between inputs from pads on one foot. Second, although there was in the interpositus nucleus a considerable topographical admixture of neurons with dominant forelimb or hindlimb inputs, the axonal projections of these neurons were apparently unscrambled on the way to the target RN neurons, so as to deliver the somatotopic specificities observed for two classes of RN neurons; those projecting down the spinal cord beyond L2 level, and those projecting to C2 but not L2. Finally, there is a general discussion of motor control with reference to the pathway; pars intermedia of anterior lobe of cerebellum leads to interpositus nucleus leads to red nucleus leads to rubrospinal tract leads to spinal motoneurons.

Animals↗

PubMed2024

Global and local ancestry estimation in a captive baboon colony.

The last couple of decades have highlighted the importance of studying hybridization, particularly among primate species, as it allows us to better understand our own evolutionary trajectory. Here, we report on genetic ancestry estimates using dense, full genome data from 881 olive (Papio anubus), yellow (Papio cynocephalus), or olive-yellow crossed captive baboons from the Southwest National Primate Research Center. We calculated global and local ancestry information, imputed low coverage genomes (n = 830) to improve marker quality, and updated the genetic resources of baboons available to assist future studies. We found evidence of historical admixture in some putatively purebred animals and identified errors within the Southwest National Primate Research Center pedigree. We also compared the outputs between two different phasing and imputation pipelines along with two different global ancestry estimation software. There was good agreement between the global ancestry estimation software, with R2 > 0.88, while evidence of phase switch errors increased depending on what phasing and imputation pipeline was used. We also generated updated genetic maps and created a concise set of ancestry informative markers (n = 1,747) to accurately obtain global ancestry estimates.

Animals↗

PubMed2026

Suggestive genome-wide associations with inflammatory biomarkers in an admixed population, including a missense variant in the OR6K6 olfactory receptor gene associated with MCP-1.

BACKGROUND: Chronic low-grade inflammation drives cardiometabolic diseases and has a strong genetic basis. Most genome-wide association studies (GWAS) have focused on European populations, limiting knowledge of the genetic influences on inflammation in admixed populations such as those in Brazil. METHODS: This study is part of the cross-sectional ISA Capital Health Survey. It uses data from the 2015 ISA Nutrition cohort, which measured biochemical, genetic, anthropometric, and lifestyle factors in a probabilistic sample of São Paulo residents. Genomic DNA was extracted from 841 individuals. Genotyping was performed using the Axiom 2.0 Precision Medicine Research Array. After quality control and missing data exclusion, 244,338 SNPs from 638 individuals remained for GWAS-based association analysis with eight inflammatory biomarkers. Models were adjusted for sex, age, age2, overweight, and the first two principal components of ancestry. RESULTS: Most participants were male (53%) and not overweight (55%). The median age was 49, and 38% were older adults. In the genome-wide analysis of TNF-α, IL-10, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and adiponectin, 12 SNPs were significantly associated, most of which were intronic. Notably, one signal mapped to the missense variant rs16841009 in the olfactory receptor gene OR6K6. This variant was associated with MCP-1, suggesting a possible involvement in inflammatory responses. CONCLUSIONS: We identified new SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population, including a missense variant in an olfactory receptor gene linked to MCP-1. This association may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.

Humans↗