Jeremy J. Martinson

Estimating African American Admixture Proportions by Use of Population-Specific Alleles

We analyzed the European genetic contribution to 10 populations of African descent in the United States (Maywood, Illinois; Detroit; New York; Philadelphia; Pittsburgh; Baltimore; Charleston, South Carolina; New Orleans; and Houston) and in Jamaica, using nine autosomal DNA markers. These markers either are population-specific or show frequency differences >45% between the parental populations and are thus especially informative for admixture. European genetic ancestry ranged from 6.8% (Jamaica) to 22.5% (New Orleans). The unique utility of these markers is reflected in the low variance associated with these admixture estimates (SEM 1.3%-2.7%). We also estimated the male and female European contribution to African Americans, on the basis of informative mtDNA (haplogroups H and L) and Y Alu polymorphic markers. Results indicate a sex-biased gene flow from Europeans, the male contribution being substantially greater than the female contribution. mtDNA haplogroups analysis shows no evidence of a significant maternal Amerindian contribution to any of the 10 populations. We detected significant nonrandom association between two markers located 22 cM apart (FY-null and AT3), most likely due to admixture linkage disequilibrium created in the interbreeding of the two parental populations. The strength of this association and the substantial genetic distance between FY and AT3 emphasize the importance of admixed populations as a useful resource for mapping traits with different prevalence in two parental populations.

Copy number variation of KIR genes influences HIV-1 control

The authors that the number of activating and inhibitory KIR genes varies between individuals and plays a role in the regulation of immune mechanisms that determine HIV-1 control.

Mitochondrial and Nuclear Genetic Relationships among Pacific Island and Asian Populations

Mitochondrial and autosomal short tandem-repeat (STR) genetic distances among 28 Pacific Island and Asian populations are significantly correlated (r=.25, P<.01) but describe distinct patterns of relationships. Maternally inherited-mtDNA data suggest that Remote Oceanic Islanders originated in island Southeast Asia. In contrast, biparental STR data reveal substantial genetic affinities between Remote Oceanic Islanders and Near Oceanic populations from highland Papua New Guinea and Australia. The low correlation between maternal and biparental genetic markers from the same individuals may reflect differences in genome-effective population sizes or in sex-biased gene flow. To explore these possibilities, we have examined genetic diversity, gene flow, and correlations among genetic, linguistic, and geographic distances within four sets of populations representing potential geographic and cultural spheres of interaction. GST estimates (a measure of genetic differentiation inversely proportional to gene flow) from mtDNA sequences vary between 0.13 and 0.39 and are typically five times greater than GST estimates from STR loci (0.05-0.08). Significant correlations (r>.5, P<.05) between maternal genetic and linguistic distances are coincident with high mtDNA GST estimates (>0.38). Thus, genetic and linguistic distances may coevolve, and their correspondence may be preserved under conditions of genetic isolation. A significant correlation (r=.65, P<.01) between biparental genetic and geographic distances is coincident with a low STR GST estimate (0.05), indicating that isolation by distance is observed under conditions of high nuclear-gene flow. These results are consistent with an initial settlement of Remote Oceania from island Southeast Asia and with extensive postcolonization male-biased gene flow with Near Oceania.

Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Variants Are Associated With Chronic Pancreatitis in Patients Without Cystic Fibrosis

BACKGROUND & AIMS Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor SPINK1 further increase the risk of pancreatitis in these patients. METHODS We screened patients and controls for variants in SPINK1 associated with risk of chronic pancreatitis and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, 150 unrelated controls, 375 additional controls for limited genotyping. CFTR wild-type and p.R75Q were cloned and expressed in HEK293 cells, and relative conductances of HCO(3)(-) and Cl(-) were measured. RESULTS SPINK1 variants were identified in 36% of subjects and 3% of controls (odds ratio [OR], 18.1). One variant of CFTR not associated with CF, p.R75Q, was found in 16% of subjects and 5.3% of controls (OR, 3.4). Coinheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.38% of controls (OR, 25.1). Patch-clamp recordings of cells that expressed CFTR p.R75Q showed normal chloride currents but significantly reduced bicarbonate currents (P = .0001). CONCLUSIONS The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk of pancreatitis. Coinheritance of p.R75Q or CF causing CFTR variants with SPINK1 variants significantly increases the risk of ICP.

Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective haplotype

Objectives:Several natural polymorphisms in the genes for the human CC-chemokine receptors CCR5 and CCR2 are associated with HIV-1 disease. The CCR2-64I genetic variant [a G to A substitution resulting in a valine (V) to isoleucine (I) change at position 64] is in strong linkage disequilibrium with a mutation within the CCR5 regulatory region (CCR5-59653T). Individuals with two CCR2-64I alleles are not resistant to sexual transmission of HIV-1, but progress significantly more slowly to HIV-1 disease. It is therefore important to determine the global distributions of CCR2-64I and CCR5-59653T genetic variants and define the degree of linkage between them. Design and methods:We have developed molecular beacon-based, real-time PCR allele discrimination assays for all three chemokine receptor mutations, and used these spectral genotyping assays to genotype 3923 individuals from a globally distributed set of 53 populations. Results:CCR2-64I and CCR5-59653T genetic variants are found in almost all populations studied: their allele frequencies are greatest (∼35%) in Africa and Asia but decrease in Northern Europe. We confirm that CCR2-64I is in strong linkage disequilibrium with CCR5-59653T (96.92% of individuals had the same genotype for both CCR2-64I and CCR5-59653T polymorphisms). Conclusions:The greater geographical distribution of the CCR2-64I/CCR5-59653T haplotype compared with that of CCR5-Δ32 suggests that it is a much older mutation whose origin predates the dispersal of modern humans.

CCL3L1 and HIV/AIDS susceptibility.

Keywords: Gene Dosage Note: Letter / Comment in: Nat Med. 2009 Oct;15(10):1112-5 and Nat Med. 2009 Oct;15(10):1127-9 and Nat Med. 2009 Oct;15(10):1117-20 / Comment on: Nat Med. 2008 Apr;14(4):413-20 Reference EPFL-ARTICLE-165167doi:10.1038/nm1009-1110 Record created on 2011-04-19, modified on 2016-08-09

Multistage Genomewide Association Study Identifies a Locus at 1q41 Associated with Rate of HIV-1 Disease Progression to Clinical AIDS

BACKGROUND A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study. METHODS The discovery stage comprised 156 individuals from the Multicenter AIDS Cohort Study, enriched with rapid and long-term nonprogressors to increase statistical power. This was followed by replication tests of putatively associated genotypes in an independent population of 590 HIV-1-infected seroconverters. RESULTS Significant associations with delayed AIDS progression were observed in a haplotype located at 1q41, 36 kb upstream of PROX1 on chromosome 1 (relative hazard ratio, 0.69; Fishers combined P = 6.23 X 10(-7)). This association was replicated further in an analysis stratified by transmission mode, with the effect consistent in sexual or mucosal and parenteral transmission (relative hazard ratios, 0.72 and 0.63, respectively; combined P = 1.63 X 10(-6)). CONCLUSIONS This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-gamma expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. This study adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS among HIV-1-infected individuals, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis.

miR-17-92 expression in differentiated T cells - implications for cancer immunotherapy

BackgroundType-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated.MethodsWe performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells.ResultsOur initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-γ production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD).ConclusionThe type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy.

MIF (Macrophage Migration Inhibitory Factor) Promoter Polymorphisms and Susceptibility to Severe Malarial Anemia

BACKGROUND Severe malarial anemia (SMA) resulting from Plasmodium falciparum infection is one of the leading causes of childhood mortality in sub-Saharan Africa. The innate immune mediator macrophage migration inhibitory factor (MIF) plays a critical role in the pathogenesis of SMA. METHODS To investigate the influence of MIF genetic variation on susceptibility to SMA, haplotypes of the MIF -173G/C and -794CATT5-8 polymorphisms were examined in a cohort of Kenyan children. RESULTS A statistically significant relationship between increasing frequencies of longer CATT repeats at -794 and increasing severity of malarial anemia was observed. In addition, there was a strong association between lower MIF concentrations and longer CATT repeats. Multivariate logistic regression analyses demonstrated that the 6G haplotype (ie, MIF -794CATT6/-173G) was associated with protection against SMA, whereas carriers of the 7C or 8C haplotype had increased risk of developing SMA. Furthermore, carriers of the 7C or 8C haplotype had reduced plasma MIF levels during acute disease. CONCLUSIONS The findings demonstrate that variation in the MIF promoter influences susceptibility to SMA and peripheral MIF production. However, the MIF -173 and -794 polymorphisms appear to have both independent and interactive effects on different measures of disease severity, suggesting that MIF plays a complex role in malarial pathogenesis.

Genotyping Schemes for Polyomavirus BK, Using Gene-Specific Phylogenetic Trees and Single Nucleotide Polymorphism Analysis

ABSTRACT BK virus (BKV) genotyping has been historically based on nucleotides 1744 to 1812 in the VP1 gene. We reevaluated this practice by making BKV whole-genome and gene-specific phylogenetic trees as well as performing single nucleotide polymorphism (SNP) analysis of 162 sequences available in the public domain. It was found that currently known BKV subtypes and subgroups can no longer be reliably determined by sequencing certain partial gene sequences. Phylogenetic trees based on large T-antigen (LTA) allow separation of subtype I into subgroups Ia, Ib1, Ib2, and Ic, with bootstrap values of 100%, which are better than bootstraps obtained using VP1 sequences (bootstrap values of 71 to 97%). Subtype IV can be subdivided into subgroups, but LTA bootstrap values (33 to 80%) are lower than those obtained by whole-genome analysis (68 to 87%). Subtypes V and VI provisionally identified earlier on the basis of more limited sequence data are better classified as subgroups Ib2 and Ib1, respectively. LTA positions 3634, 3772, 3934, and 4339 can serve as a minimal SNP set to distinguish between the four major BKV subtypes. No subtype II-, IVa-, or IVb-defining SNPs are available in the VP1 gene. However, the overall congruence of viral strain classification based on either VP1 or LTA phylogenetic analysis indicates that these two areas of the viral genome are genetically linked. Interstrain genetic recombination between distant loci in the VP1 and LTA areas is not a common event.