Brian R Hallmark

Interests

No activities entered.

Courses

Scholarly Contributions

Journals/Publications

• Chilton, F., Hallmark, B., Yang, C., Veenstra, J., Bartz, T., Pahl, M., Chen, Y. I., Westra, J., Steffen, L., Brown, C., Siscovick, D., Tsai, M., Wood, A., Rich, S., Smith, C., O'Connor, T., Mozaffarian, D., Grant, S., Tintle, N., , Lemaitre, R., et al. (2023). Genome-Wide Association Studies and fine-mapping of genomic loci for n-3 and n-6 Polyunsaturated Fatty Acids in Hispanic American and African American Cohorts. Commun Biology 2023 Aug 16. doi:doi: 10.1038/s42003-023-05219-w
• Garcia, D. O., Chilton, F., Thomson, C. A., Hallmark, B., & Lopez-Pentecost, M. (2023). Association between Dietary Fatty Acid Intake and Liver Steatosis and Fibrosis in a Sample of Mexican-Origin Hispanic Adults with Overweight or Obesity. International Journal of Environmental Research and Public Health, 20(4), 3103. doi:10.3390/ijerph20043103
• Hara, A., Lu, E., Johnstone, L., Wei, M., Sun, S., Hallmark, B., Watkins, J. C., Zhang, H. H., Yao, G., & Chilton, F. H. (2023). Identification of an allele-specific transcription factor binding interaction that regulates gene expression. bioRxiv : the preprint server for biology.
  More info

  The secreted phospholipase A (sPLA ) isoform, sPLA -IIA, has been implicated in a variety of diseases and conditions, including bacteremia, cardiovascular disease, COVID-19, sepsis, adult respiratory distress syndrome, and certain cancers. Given its significant role in these conditions, understanding the regulatory mechanisms impacting its levels is crucial. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs), including rs11573156, that are associated with circulating levels of sPLA -IIA. Through Genotype-Tissue Expression (GTEx), 234 expression quantitative trait loci (eQTLs) were identified for the gene that encodes for sPLA -IIA, . SNP2TFBS ( https://ccg.epfl.ch/snp2tfbs/ ) was utilized to ascertain the binding affinities between transcription factors (TFs) to both the reference and alternative alleles of identified SNPs. Subsequently, ChIP-seq peaks highlighted the TF combinations that specifically bind to the SNP, rs11573156. SP1 emerged as a significant TF/SNP pair in liver cells, with rs11573156/SP1 interaction being most prominent in liver, prostate, ovary, and adipose tissues. Further analysis revealed that the upregulation of PLA2G2A transcript levels through the rs11573156 variant was affected by tissue SP1 protein levels. By leveraging an ordinary differential equation, structured upon Michaelis-Menten enzyme kinetics assumptions, we modeled the PLA2G2A transcription's dependence on SP1 protein levels, incorporating the SNP's influence. Collectively, these data strongly suggest that the binding affinity differences of SP1 for the different rs11573156 alleles can influence expression. This, in turn, can modulate sPLA2-IIA levels, impacting a wide range of human diseases.
• Chilton, F., Manichaikul, A., Yang, C., O'Connor, T. D., Johnstone, L., Blomquist, S., Bridgewater, S. J., Mathias, R. A., & Hallmark, B. R. (2022). Interpreting Clinical Trials With Omega-3 Supplements in the Context of Ancestry and FADS Genetic Variation. Frontiers in Nutrition. doi:https://doi.org/10.3389/fnut.2021.808054
• Garcia, D., Chilton, F., Hallmark, B., Lopez-Pentecost, M., & Thomson, C. (2022). Abstract 5956: Relationship between fatty acid intake and liver steatosis and fibrosis among overweight and obese Mexican-origin adults. Cancer Research, 82(12_Supplement), 5956-5956. doi:10.1158/1538-7445.am2022-5956
• Fernandez, M. L., Blomquist, S. A., Hallmark, B., & Chilton, F. H. (2021). Omega-3 Supplementation and Heart Disease: A Population-Based Diet by Gene Analysis of Clinical Trial Outcomes. Nutrients, 13(7).
  More info

  Omega-3 (-3) polyunsaturated fatty acids (PUFA) and their metabolites have long been recognized to protect against inflammation-related diseases including heart disease. Recent reports present conflicting evidence on the effects of -3 PUFAs on major cardiovascular events including death. While some studies document that -3 PUFA supplementation reduces the risk for heart disease, others report no beneficial effects on heart disease composite primary outcomes. Much of this heterogeneity may be related to the genetic variation in different individuals/populations that alters their capacity to synthesize biologically active -3 and omega 6 (-6) PUFAs and metabolites from their 18 carbon dietary precursors, linoleic acid (LA, 18:2 -6) and alpha-linolenic (ALA, 18:3, -3). Here, we discuss the role of a gene-by-dietary PUFA interaction model that takes into consideration dietary exposure, including the intake of LA and ALA, -3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in determining the efficacy of -3 PUFA supplementation. We also review recent clinical trials with -3 PUFA supplementation and coronary heart disease in the context of what is known about fatty acid desaturase ( gene-by-dietary PUFA interactions. Given the dramatic differences in the frequencies of variants that impact the efficiency of -3 and -6 PUFA biosynthesis, and their downstream signaling products among global and admixture populations, we conclude that large clinical trials utilizing "one size fits all" -3 PUFA supplementation approaches are unlikely to show effectiveness. However, evidence discussed in this review suggests that -3 PUFA supplementation may represent an important opportunity where precision interventions can be focused on those populations that will benefit the most from -3 PUFA supplementation.
• Hallmark, B. R. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality. Journal of Clinical Investigation.
• Hallmark, B. R. (2021). Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations. Communications Biology.
• Hallmark, B. R. (2021). Omega-3 Supplementation and Heart Disease: A Population-Based Diet by Gene Analysis of Clinical Trial Outcomes. Nutrients.
• Snider, J. M., You, J. K., Wang, X., Snider, A. J., Hallmark, B., Seeds, M. C., Sergeant, S., Johnstone, L., Wang, Q., Sprissler, R., Zhang, H. H., Luberto, C., Kew, R. R., Hannun, Y. A., McCall, C. E., Yao, G., Del Poeta, M., & Chilton, F. H. (2021). Group IIA Secreted Phospholipase A Plays a Central Role in the Pathobiology of COVID-19. medRxiv : the preprint server for health sciences.
  More info

  There is an urgent need to identify cellular and molecular mechanisms responsible for severe COVID-19 disease accompanied by multiple organ failure and high mortality rates. Here, we performed untargeted/targeted lipidomics and focused biochemistry on 127 patient plasma samples, and showed high levels of circulating, enzymatically active secreted phospholipase A Group IIA (sPLA -IIA) in severe and fatal COVID-19 disease compared with uninfected patients or mild illness. Machine learning demonstrated that sPLA -IIA effectively stratifies severe from fatal COVID-19 disease. We further introduce a PLA-BUN index that combines sPLA -IIA and blood urea nitrogen (BUN) threshold levels as a critical risk factor for mitochondrial dysfunction, sustained inflammatory injury and lethal COVID-19. With the availability of clinically tested inhibitors of sPLA -IIA, our study opens the door to a precision intervention using indices discovered here to reduce COVID-19 mortality.
• Snider, J. M., You, J. K., Wang, X., Snider, A. J., Hallmark, B., Zec, M. M., Seeds, M. C., Sergeant, S., Johnstone, L., Wang, Q., Sprissler, R., Carr, T. F., Lutrick, K., Parthasarathy, S., Bime, C., Zhang, H. H., Luberto, C., Kew, R. R., Hannun, Y. A., , Guerra, S., et al. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality. The Journal of clinical investigation, 131(19).
  More info

  There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
• Wright, A. L., Hallmark, B., Wright, A. L., Wegienka, G., Stern, D. A., Ownby, D. R., Ober, C., O'connor, G. T., Nicolae, D. L., Myers, J. B., Miller, R. L., Mendonca, E. A., Martinez, F. D., Lemanske, R. F., Jackson, D. J., Hoepner, L., Hershey, G. K., Havstad, S., Hallmark, B., , Gress, L., et al. (2021). Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood.. American journal of respiratory and critical care medicine, 203(7), 864-870. doi:10.1164/rccm.202003-0820oc
  More info

  Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored.Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry.Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children.Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children.Conclusions: These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.
• Yang, C., Hallmark, B., Chai, J. C., O'Connor, T. D., Reynolds, L. M., Wood, A. C., Seeds, M., Chen, Y. I., Steffen, L. M., Tsai, M. Y., Kaplan, R. C., Daviglus, M. L., Mandarino, L. J., Fretts, A. M., Lemaitre, R. N., Coletta, D. K., Blomquist, S. A., Johnstone, L. M., Tontsch, C., , Qi, Q., et al. (2021). Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations. Communications biology, 4(1), 918.
  More info

  Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.
• Zec, M., Yang, C., Tsai, M. Y., Sergeant, S., Schembre, S. M., Rich, S. S., O'connor, T. D., Mathias, R. A., Manichaikul, A., Johnstone, L. M., Hallmark, B., Chilton, F. H., Bridgewater, S. J., & Blomquist, S. (2021). Interpreting Clinical Trials With Omega-3 Supplements in the Context of Ancestry and FADS Genetic Variation.. Frontiers in nutrition, 8, 808054. doi:10.3389/fnut.2021.808054
  More info

  Human diets in developed countries such as the US have changed dramatically over the past 75 years, leading to increased obesity, inflammation, and cardiometabolic dysfunction. Evidence over the past decade indicates that the interaction of genetic variation with changes in the intake of 18-carbon essential dietary omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, has impacted numerous molecular and clinical phenotypes. Interactions are particularly relevant with the FADS1 and FADS2 genes, which encode key fatty acid desaturases in the pathway that converts LA and ALA to their long chain (≥20 carbons), highly unsaturated fatty acid (HUFA) counterparts. These gene by nutrient interactions affect the levels and balance of n-6 and n-3 HUFA that in turn are converted to a wide array of lipids with signaling roles, including eicosanoids, docosanoids, other oxylipins and endocannabinoids. With few exceptions, n-6 HUFA are precursors of pro-inflammatory/pro-thrombotic signaling lipids, and n-3 HUFA are generally anti-inflammatory/anti-thrombotic. We and others have demonstrated that African ancestry populations have much higher frequencies (vs. European-, Asian- or indigenous Americas-ancestry populations) of a FADS "derived" haplotype that is associated with the efficient conversion of high levels of dietary n-6 PUFA to pro-inflammatory n-6 HUFA. By contrast, an "ancestral" haplotype, carrying alleles associated with a limited capacity to synthesize HUFA, which can lead to n-3 HUFA deficiency, is found at high frequency in certain Hispanic populations and is nearly fixed in several indigenous populations from the Americas. Based on these observations, a focused secondary subgroup analysis of the VITAL n-3 HUFA supplementation trial stratifying the data based on self-reported ancestry revealed that African Americans may benefit from n-3 HUFA supplementation, and both ancestry and FADS variability should be factored into future clinical trials design.
• Hallmark, B., Coletta, D. K., Chilton, F. H., Yang, C., Rich, S. S., Manichaikul, A. W., Mandarino, L. J., Coletta, D. K., & Blomquist, S. (2020). Abstract MP67: Fatty Acid Desaturase Gene-induced Omega-3 Deficiency In Amerindian-Ancestry Hispanic Populations. Circulation, 141(Suppl_1). doi:10.1161/circ.141.suppl_1.mp67
  More info

  Hispanic populations in the US have increased risk of obesity, elevated circulating triglycerides, nonalcoholic fatty liver disease, and diabetes. Our previous studies suggest that ancestry-related differences in the frequency of variants in the fatty acid desaturase ( FADS) gene cluster in the context of the modern Western diet can lead to inadequate circulating and tissues levels of n-3 long-chain (LC-; ≥ 20 carbons) polyunsaturated fatty acids (PUFA); these deficiencies in turn have the capacity to increase metabolic disease risk. Specifically, we and others have demonstrated Amerindian (AI)-Ancestry populations have high frequencies of FADS gene variants that may lead to less efficient n-3 LC-PUFA biosynthesis. To test this hypothesis, concentrations of fatty acids, including LC-PUFAs in plasma phospholipids were analyzed in 1,102 Hispanic American participants from Multi-Ethnic Study of Atherosclerosis (MESA) cohort, which represent six Hispanic subgroups based on self-reported region of origin: Central America, South America, Mexico, Cuba, Dominican Republic, and Puerto Rico. These data revealed a striking inverse relationship between genome-wide AI-ancestry and levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Additional analyses revealed that the genotype at FADS SNP rs174537, for which the frequency of the T allele increases with AI-ancestry, could primarily explain the associations. There also was a strong association between the number of T alleles (additive model) at rs174537 and circulating triglycerides (18.5 mg/dL per T allele; P =2.0 x 10 -5 ) as well as an important marker of vascular inflammation sICAM-1 (β=12.7 ng/mL, P =0.02). We also genotyped the FADS SNP, rs174537, in a separate adult Arizona Hispanic cohort (Arizona Insulin Resistance [AIR] registry) and compared the FADS genotypic frequencies with other racial/ethnic groups. Importantly, the TT genotype associated with limited LC-PUFA biosynthesis ranges from
• Hallmark, B., Coletta, D. K., Chilton, F. H., Yang, C., Rich, S. S., Manichaikul, A. W., Mandarino, L. J., Hallmark, B., Chilton, F. H., & Blomquist, S. (2020). Fatty Acid Desaturase Gene‐Induced Omega‐3 Deficiency in Amerindian‐Ancestry Hispanic Populations. The FASEB Journal, 34(S1), 1-1. doi:10.1096/fasebj.2020.34.s1.06389
• Hallmark, B., Wegienka, G., Havstad, S., Billheimer, D., Ownby, D., Mendonca, E. A., Gress, L., Stern, D. A., Myers, J. B., Khurana Hershey, G. K., Hoepner, L., Miller, R. L., Lemanske, R. F., Jackson, D. J., Gold, D. R., O'Connor, G. T., Nicolae, D. L., Gern, J. E., Ober, C., , Wright, A. L., et al. (2020). Chromosome 17q12-21 Variants are Associated with Multiple Wheezing Phenotypes in Childhood. American journal of respiratory and critical care medicine.
  More info

  Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored.
• Mullins, V. A., Bresette, W., Johnstone, L., Hallmark, B., & Chilton, F. H. (2020). Genomics in Personalized Nutrition: Can You "Eat for Your Genes"?. Nutrients, 12(10).
  More info

  Genome-wide single nucleotide polymorphism (SNP) data are now quickly and inexpensively acquired, raising the prospect of creating personalized dietary recommendations based on an individual's genetic variability at multiple SNPs. However, relatively little is known about most specific gene-diet interactions, and many molecular and clinical phenotypes of interest (e.g., body mass index [BMI]) involve multiple genes. In this review, we discuss direct to consumer genetic testing (DTC-GT) and the current potential for precision nutrition based on an individual's genetic data. We review important issues such as dietary exposure and genetic architecture addressing the concepts of penetrance, pleiotropy, epistasis, polygenicity, and epigenetics. More specifically, we discuss how they complicate using genotypic data to predict phenotypes as well as response to dietary interventions. Then, several examples (including caffeine sensitivity, alcohol dependence, non-alcoholic fatty liver disease, obesity/appetite, cardiovascular, Alzheimer's disease, folate metabolism, long-chain fatty acid biosynthesis, and vitamin D metabolism) are provided illustrating how genotypic information could be used to inform nutritional recommendations. We conclude by examining ethical considerations and practical applications for using genetic information to inform dietary choices and the future role genetics may play in adopting changes beyond population-wide healthy eating guidelines.
• Ober, C., McKennan, C. G., Magnaye, K. M., Altman, M. C., Washington, C., Stanhope, C., Naughton, K. A., Rosasco, M. G., Bacharier, L. B., Billheimer, D., Gold, D. R., Gress, L., Hartert, T., Havstad, S., Khurana Hershey, G. K., Hallmark, B., Hogarth, D. K., Jackson, D. J., Johnson, C. C., , Kattan, M., et al. (2020). Expression quantitative trait locus fine mapping of the 17q12-21 asthma locus in African American children: a genetic association and gene expression study. The Lancet. Respiratory medicine, 8(5), 482-492.
  More info

  African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus.
• Reynolds, L. M., Dutta, R., Seeds, M. C., Lake, K. N., Hallmark, B., Mathias, R. A., Howard, T. D., & Chilton, F. H. (2020). FADS genetic and metabolomic analyses identify the ∆5 desaturase (FADS1) step as a critical control point in the formation of biologically important lipids. Scientific reports, 10(1), 15873.
  More info

  Humans have undergone intense evolutionary selection to optimize their capacity to generate necessary quantities of long chain (LC-) polyunsaturated fatty acid (PUFA)-containing lipids. To better understand the impact of genetic variation within a locus of three FADS genes (FADS1, FADS2, and FADS3) on a diverse family of lipids, we examined the associations of 247 lipid metabolites (including four major classes of LC-PUFA-containing molecules and signaling molecules) with common and low-frequency genetic variants located within the FADS locus. Genetic variation in the FADS locus was strongly associated (p 
• Sergeant, S., Hallmark, B., Mathias, R. A., Mustin, T. L., Ivester, P., Bohannon, M. L., Ruczinski, I., Johnstone, L., Seeds, M. C., & Chilton, F. H. (2020). Prospective clinical trial examining the impact of genetic variation in FADS1 on the metabolism of linoleic acid- and ɣ-linolenic acid-containing botanical oils. The American journal of clinical nutrition, 111(5), 1068-1078.
  More info

  Unexplained heterogeneity in clinical trials has resulted in questions regarding the effectiveness of ɣ-linolenic acid (GLA)-containing botanical oil supplements. This heterogeneity may be explained by genetic variation within the fatty acid desaturase (FADS) gene cluster that is associated with circulating and tissue concentrations of arachidonic acid (ARA) and dihomo-ɣ-linolenic acid (DGLA), both of which may be synthesized from GLA and result in proinflammatory and anti-inflammatory metabolites, respectively.
• Snider, A. J., Seeds, M. C., Johnstone, L., Snider, J. M., Hallmark, B., Dutta, R., Moraga Franco, C., Parks, J. S., Bensen, J. T., Broeckling, C. D., Mohler, J. L., Smith, G. J., Fontham, E. T., Lin, H. K., Bresette, W., Sergeant, S., & Chilton, F. H. (2020). Identification of Plasma Glycosphingolipids as Potential Biomarkers for Prostate Cancer (PCa) Status. Biomolecules, 10(10).
  More info

  Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in United States men. Controversy continues over the effectiveness of prostate-specific antigen (PSA) for distinguishing aggressive from indolent PCa. There is a critical need for more specific and sensitive biomarkers to detect and distinguish low- versus high-risk PCa cases. Discovery metabolomics were performed utilizing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) on plasma samples from 159 men with treatment naïve prostate cancer participating in the North Carolina-Louisiana PCa Project to determine if there were metabolites associated with aggressive PCa. Thirty-five identifiable plasma small molecules were associated with PCa aggressiveness, 15 of which were sphingolipids; nine common molecules were present in both African-American and European-American men. The molecules most associated with PCa aggressiveness were glycosphingolipids; levels of trihexosylceramide and tetrahexosylceramide were most closely associated with high-aggressive PCa. The Cancer Genome Atlas was queried to determine gene alterations within glycosphingolipid metabolism that are associated with PCa and other cancers. Genes that encode enzymes associated with the metabolism of glycosphingolipids were altered in 12% of PCa and >30% of lung, uterine, and ovarian cancers. These data suggest that the identified plasma (glyco)sphingolipids should be further validated for their association with aggressive PCa, suggesting that specific sphingolipids may be included in a diagnostic signature for PCa.
• Hallmark, B., Hallmark, B., Billheimer, D., Billheimer, D., Martinez, F. D., Martinez, F. D., Gerald, L. B., Gerald, L. B., Gerald, J. K., & Gerald, J. K. (2019). Are Latino children of Mexican origin with asthma less responsive to inhaled corticosteroids than white children?. The journal of allergy and clinical immunology. In practice, 7(7), 2419-2421. doi:10.1016/j.jaip.2019.02.032
• Hallmark, B., Hammer, M. F., Watkins, J. C., Osipova, L. P., Karafet, T. M., & Hsieh, P. (2019). Genomic Evidence of Local Adaptation to Climate and Diet in Indigenous Siberians.. Molecular biology and evolution, 36(2), 315-327. doi:10.1093/molbev/msy211
  More info

  The indigenous inhabitants of Siberia live in some of the harshest environments on earth, experiencing extended periods of severe cold temperatures, dramatic variation in photoperiod, and limited and highly variable food resources. While the successful long-term settlement of this area by humans required multiple behavioral and cultural innovations, the nature of the underlying genetic changes has generally remained elusive. In this study, we used a three-part approach to identify putative targets of positive natural selection in Siberians. We first performed selection scans on whole exome and genome-wide single nucleotide polymorphism array data from multiple Siberian populations. We then annotated candidates in the tails of the empirical distributions, focusing on candidates with evidence linking them to biological processes and phenotypes previously identified as relevant to adaptation in circumpolar groups. The top candidates were then genotyped in additional populations to determine their spatial allele frequency distributions and associations with climate variables. Our analysis reveals missense mutations in three genes involved in lipid metabolism (PLA2G2A, PLIN1, and ANGPTL8) that exhibit genomic and spatial patterns consistent with selection for cold climate and/or diet. These variants are unified by their connection to brown adipose tissue and may help to explain previously observed physiological differences in Siberians such as low serum lipid levels and increased basal metabolic rate. These results support the hypothesis that indigenous Siberians have genetically adapted to their local environment by selection on multiple genes.
• Hallmark, B., Savina, O. V., Osipova, L. P., Karafet, T. M., & Hammer, M. F. (2018). Siberian genetic diversity reveals complex origins of the Samoyedic-speaking populations.. American journal of human biology : the official journal of the Human Biology Council, 30(6), e23194. doi:10.1002/ajhb.23194
  More info

  We examined autosomal genome-wide SNPs and Y-chromosome data from 15 Siberian and 12 reference populations to study the affinities of Siberian populations, and to address hypotheses about the origin of the Samoyed peoples..Samples were genotyped for 567 096 autosomal SNPs and 147 Y-chromosome polymorphic sites. For several analyses, we used 281 093 SNPs from the intersection of our data with publicly available ancient Siberian samples. To examine genetic relatedness among populations, we applied PCA, FST , TreeMix, and ADMIXTURE analyses. To explore the potential effect of demography and evolutionary processes, the distribution of ROH and IBD sharing within population were studied..Analyses of autosomal and Y-chromosome data reveal high differentiation of the Siberian groups. The Siberian populations have a large proportion of their genome in ROH and IBD segments. Several populations (ie, Nganasans, Evenks, Yukagirs, and Koryaks) do not appear to have experienced admixture with other Siberian populations (ie, producing only positive f3), while for the other tested populations the composition of mixing sources always included Nganasans or Evenks. The Nganasans from the Taymyr Peninsula demonstrate the greatest level of shared shorter ROH and IBD with nearly all other Siberian populations..Autosomal SNP and Y-chromosome data demonstrate that Samoyedic populations differ significantly in their genetic composition. Genetic relationship is observed only between Forest and Tundra Nentsi. Selkups are affiliated with the Kets from the Yenisey River, while the Nganasans are separated from their linguistic neighbors, showing closer affinities with the Evenks and Yukagirs.
• Hallmark, B., Fisher, J. M., Avery, R., Billheimer, D., Runyan, R. B., Konhilas, J. P., Schipper, D., Rao, P., Pilikian, T., Marsh, K. M., Konhilas, J. P., Khalpey, Z., Johnson, K., Hallmark, B., Fisher, J. M., Duncker, D. J., & Avery, R. (2017). Abstract 14670: Human Amniotic Patch Placement During Cardiac Surgery Reduces Post-Operative Atrial Fibrillation. Circulation.
  More info

  Introduction: Atrial fibrillation after cardiac surgery occurs in approximately one third of patients and is associated with increased morbidity and mortality. Inflammation and oxidative stress may...
• Hallmark, B., Watkins, J. C., Osipova, L. P., Karafet, T. M., Hsieh, P., Hammer, M. F., & Gutenkunst, R. N. (2017). Exome Sequencing Provides Evidence of Polygenic Adaptation to a Fat-Rich Animal Diet in Indigenous Siberian Populations.. Molecular biology and evolution, 34(11), 2913-2926. doi:10.1093/molbev/msx226
  More info

  Siberia is one of the coldest environments on Earth and has great seasonal temperature variation. Long-term settlement in northern Siberia undoubtedly required biological adaptation to severe cold stress, dramatic variation in photoperiod, and limited food resources. In addition, recent archeological studies show that humans first occupied Siberia at least 45,000 years ago; yet our understanding of the demographic history of modern indigenous Siberians remains incomplete. In this study, we use whole-exome sequencing data from the Nganasans and Yakuts to infer the evolutionary history of these two indigenous Siberian populations. Recognizing the complexity of the adaptive process, we designed a model-based test to systematically search for signatures of polygenic selection. Our approach accounts for stochasticity in the demographic process and the hitchhiking effect of classic selective sweeps, as well as potential biases resulting from recombination rate and mutation rate heterogeneity. Our demographic inference shows that the Nganasans and Yakuts diverged ∼12,000-13,000 years ago from East-Asian ancestors in a process involving continuous gene flow. Our polygenic selection scan identifies seven candidate gene sets with Siberian-specific signals. Three of these gene sets are related to diet, especially to fat metabolism, consistent with the hypothesis of adaptation to a fat-rich animal diet. Additional testing rejects the effect of hitchhiking and favors a model in which selection yields small allele frequency changes at multiple unlinked genes.
• Hallmark, B., Zhou, J., Zhang, M., Watkins, J. C., Tchourbanov, A., Sprissler, R., Lau, B., Johnstone, L., Ishii, A., Hirose, S., & Hammer, M. F. (2017). Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome.. PloS one, 12(7), e0180485. doi:10.1371/journal.pone.0180485
  More info

  Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.
• Orr, Y., & Hallmark, B. (2014). Folk Food Webs and the Role of Praxis in Substantive Ecological Knowledge. Human Ecology, 42(2), 339-346. doi:10.1007/s10745-013-9628-2
  More info

  In the second half of the 20th century, investigations of indigenous environmental knowledge have been the subject of broader anthropological debates over how knowledge and experience are formed. Many such approaches have focused on environmental nomenclature and taxonomy, or what Roy Ellen has called “formal lexical knowledge” (1999). Such knowledge is readily available to an ethnographer and also more easily transmitted through language between subjects. These characteristics of formal lexical knowledge have led to considerable attention given to differences in environmental knowledge between cultures and have possibly resulted in the inflation of the efficacy of language in forming knowledge. However, if a different form of environmental knowledge is examined are there differences that emerge within communities and other processes beyond symbolic systems that shape knowledge? To address these questions, individuals in two Balinese agricultural communities were asked to construct food webs by linking photos of plant and animal species according to ecological interaction. The results showed significant variation in subjects’ knowledge by gender, which corresponds to labor experience in Balinese wet rice agricultural systems. By shifting attention toward emic models of ecological interactions, this article attempts to demonstrate (1) that environmental knowledge differs within a single community; and, (2) the role of labor experience or praxis has in forming environmental knowledge.
• Hallmark, B., Tumonggor, M. K., Sudoyo, H., Lansing, J. S., Karafet, T. M., Hammer, M. F., & Cox, M. P. (2013). The Indonesian archipelago: an ancient genetic highway linking Asia and the Pacific.. Journal of human genetics, 58(3), 165-73. doi:10.1038/jhg.2012.154
  More info

  Indonesia, an island nation linking mainland Asia with the Pacific world, hosts a wide range of linguistic, ethnic and genetic diversity. Despite the complexity of this cultural environment, genetic studies in Indonesia remain surprisingly sparse. Here, we report mitochondrial DNA (mtDNA) and associated Y-chromosome diversity for the largest cohort of Indonesians examined to date-2740 individuals from 70 communities spanning 12 islands across the breadth of the Indonesian archipelago. We reconstruct 50 000 years of population movements, from mitochondrial lineages reflecting the very earliest settlers in island southeast Asia, to Neolithic population dispersals. Historic contacts from Chinese, Indians, Arabs and Europeans comprise a noticeable fraction of Y-chromosome variation, but are not reflected in the maternally inherited mtDNA. While this historic immigration favored men, patterns of genetic diversity show that women moved more widely in earlier times. However, measures of population differentiation signal that Indonesian communities are trending away from the matri- or ambilocality of early Austronesian societies toward the more common practice of patrilocal residence today. Such sex-specific dispersal patterns remain even after correcting for the different mutation rates of mtDNA and the Y chromosome. This detailed palimpsest of Indonesian genetic diversity is a direct outcome of the region's complex history of immigration, transitory migrants and populations that have endured in situ since the region's first settlement.
• Cox, M. P., Vet, T. A., Downey, S. S., Hallmark, B., Sudoyo, H., & Lansing, J. S. (2011). An ongoing Austronesian expansion in Island Southeast Asia. Journal of Anthropological Archaeology, 30(3), 262-272. doi:10.1016/j.jaa.2011.06.004
  More info

  The Austronesian expansion into Island Southeast Asia and the Pacific was the last and most far-reaching prehistoric human migration. Austronesian languages replaced indigenous languages over nearly half the globe, yet the absolute number of Austronesian colonists was small. Recently, geneticists have identified large geographic disparities in the relative proportions of Asian ancestry across different genetic systems (NRY, mitochondrial DNA, autosomes and X chromosomes) in Austronesian-speaking societies of Island Southeast Asia and the Pacific. Surprisingly, a substantial genetic discontinuity occurs in the middle of a continuous chain of islands that form the southern arc of the Indonesian archipelago, near the geographic center of the Austronesian world. In the absence of geographic barriers to migration, this genetic boundary and swathe of Austronesian language replacement must have emerged from social behavior. Drawing on decades of comparative ethnological research inspired by F.A.E. van Wouden's structural model of Austronesian social organization, later codified by Claude Levi-Strauss as "House societies" ("societes a maison"), we propose a two-stage ethnographic model in which the appearance of matrilocal "House societies" during the initial phase of the Austronesian expansion, and the subsequent disappearance of "House societies" in lowland rice-growing regions, accounts for the observed linguistic, genetic and cultural patterns.
• Hallmark, B., Sudoyo, H., Lansing, J. S., Karafet, T. M., Hammer, M. F., Downey, S. S., & Cox, M. P. (2010). Major east-west division underlies Y chromosome stratification across Indonesia.. Molecular biology and evolution, 27(8), 1833-44. doi:10.1093/molbev/msq063
  More info

  The early history of island Southeast Asia is often characterized as the story of two major population dispersals: the initial Paleolithic colonization of Sahul approximately 45 ka ago and the much later Neolithic expansion of Austronesian-speaking farmers approximately 4 ka ago. Here, in the largest survey of Indonesian Y chromosomes to date, we present evidence for multiple genetic strata that likely arose through a series of distinct migratory processes. We genotype an extensive battery of Y chromosome markers, including 85 single-nucleotide polymorphisms/indels and 12 short tandem repeats, in a sample of 1,917 men from 32 communities located across Indonesia. We find that the paternal gene pool is sharply subdivided between western and eastern locations, with a boundary running between the islands of Bali and Flores. Analysis of molecular variance reveals one of the highest levels of between-group variance yet reported for human Y chromosome data (e.g., Phi(ST) = 0.47). Eastern Y chromosome haplogroups are closely related to Melanesian lineages (i.e., within the C, M, and S subclades) and likely reflect the initial wave of colonization of the region, whereas the majority of western Y chromosomes (i.e., O-M119*, O-P203, and O-M95*) are related to haplogroups that may have entered Indonesia during the Paleolithic from mainland Asia. In addition, two novel markers (P201 and P203) provide significantly enhanced phylogenetic resolution of two key haplogroups (O-M122 and O-M119) that are often associated with the Austronesian expansion. This more refined picture leads us to put forward a four-phase colonization model in which Paleolithic migrations of hunter-gatherers shape the primary structure of current Indonesian Y chromosome diversity, and Neolithic incursions make only a minor impact on the paternal gene pool, despite the large cultural impact of the Austronesian expansion.
• Hallmark, B., Zhivotovsky, L. A., Skorecki, K., Rosset, S., Mendez, F. L., Karafet, T. M., Hammer, M. F., Erez, T., & Behar, D. M. (2009). Extended Y chromosome haplotypes resolve multiple and unique lineages of the Jewish priesthood.. Human genetics, 126(5), 707-17. doi:10.1007/s00439-009-0727-5
  More info

  It has been known for over a decade that a majority of men who self report as members of the Jewish priesthood (Cohanim) carry a characteristic Y chromosome haplotype termed the Cohen Modal Haplotype (CMH). The CMH has since been used to trace putative Jewish ancestral origins of various populations. However, the limited number of binary and STR Y chromosome markers used previously did not provide the phylogenetic resolution needed to infer the number of independent paternal lineages that are encompassed within the Cohanim or their coalescence times. Accordingly, we have genotyped 75 binary markers and 12 Y-STRs in a sample of 215 Cohanim from diverse Jewish communities, 1,575 Jewish men from across the range of the Jewish Diaspora, and 2,099 non-Jewish men from the Near East, Europe, Central Asia, and India. While Cohanim from diverse backgrounds carry a total of 21 Y chromosome haplogroups, 5 haplogroups account for 79.5% of Cohanim Y chromosomes. The most frequent Cohanim lineage (46.1%) is marked by the recently reported P58 T->C mutation, which is prevalent in the Near East. Based on genotypes at 12 Y-STRs, we identify an extended CMH on the J-P58* background that predominates in both Ashkenazi and non-Ashkenazi Cohanim and is remarkably absent in non-Jews. The estimated divergence time of this lineage based on 17 STRs is 3,190 +/- 1,090 years. Notably, the second most frequent Cohanim lineage (J-M410*, 14.4%) contains an extended modal haplotype that is also limited to Ashkenazi and non-Ashkenazi Cohanim and is estimated to be 4.2 +/- 1.3 ky old. These results support the hypothesis of a common origin of the CMH in the Near East well before the dispersion of the Jewish people into separate communities, and indicate that the majority of contemporary Jewish priests descend from a limited number of paternal lineages.
• Downey, S. S., Hallmark, B., Cox, M. P., Norquest, P., & Lansing, J. S. (2008). Computational Feature-Sensitive Reconstruction of Language Relationships: Developing the ALINE Distance for Comparative Historical Linguistic Reconstruction*. Journal of Quantitative Linguistics, 15(4), 340-369. doi:10.1080/09296170802326681
  More info

  Abstract Historical relationships among languages are used as a proxy for social history in many non-linguistic settings, including the fields of cultural and molecular anthropology. Linguists have traditionally assembled this information using the standard comparative method. While providing extremely nuanced linguistic information, this approach is time-consuming and labor-intensive. Conversely, computational approaches are appreciably quicker, but can potentially introduce significant error. Furthermore, current methods often use cognate sets that were themselves coded by historical linguists, thus reducing the benefit of computational approaches. Here we develop a method, based on the ALINE distance, to extract feature-sensitive relationships from paired glosses, datasets that require minimal contribution from trained linguists beyond transcription from primary sources. We validate our results by comparison with data generated independently via the comparative method, and quantify error rates using co...
• Hallmark, B., Watkins, J. C., Sudoyo, H., Lansing, J. S., Karafet, T. M., Hammer, M. F., & Cox, M. P. (2008). Male dominance rarely skews the frequency distribution of Y chromosome haplotypes in human populations.. Proceedings of the National Academy of Sciences of the United States of America, 105(33), 11645-50. doi:10.1073/pnas.0710158105
  More info

  A central tenet of evolutionary social science holds that behaviors, such as those associated with social dominance, produce fitness effects that are subject to cultural selection. However, evidence for such selection is inconclusive because it is based on short-term statistical associations between behavior and fertility. Here, we show that the evolutionary effects of dominance at the population level can be detected using noncoding regions of DNA. Highly variable polymorphisms on the nonrecombining portion of the Y chromosome can be used to trace lines of descent from a common male ancestor. Thus, it is possible to test for the persistence of differential fertility among patrilines. We examine haplotype distributions defined by 12 short tandem repeats in a sample of 1269 men from 41 Indonesian communities and test for departures from neutral mutation-drift equilibrium based on the Ewens sampling formula. Our tests reject the neutral model in only 5 communities. Analysis and simulations show that we have sufficient power to detect such departures under varying demographic conditions, including founder effects, bottlenecks, and migration, and at varying levels of social dominance. We conclude that patrilines seldom are dominant for more than a few generations, and thus traits or behaviors that are strictly paternally inherited are unlikely to be under strong cultural selection.
• Hallmark, B., Norquest, P., Watkins, J. C., Sudoyo, H., Schoenfelder, J. W., Lansing, J. S., Karafet, T. M., Hammer, M. F., Gabler, B. M., Downey, S. S., & Cox, M. P. (2007). Coevolution of languages and genes on the island of Sumba, eastern Indonesia.. Proceedings of the National Academy of Sciences of the United States of America, 104(41), 16022-6. doi:10.1073/pnas.0704451104
  More info

  Numerous studies indicate strong associations between languages and genes among human populations at the global scale, but all broader scale genetic and linguistic patterns must arise from processes originating at the community level. We examine linguistic and genetic variation in a contact zone on the eastern Indonesian island of Sumba, where Neolithic Austronesian farming communities settled and began interacting with aboriginal foraging societies approximately 3,500 years ago. Phylogenetic reconstruction based on a 200-word Swadesh list sampled from 29 localities supports the hypothesis that Sumbanese languages derive from a single ancestral Austronesian language. However, the proportion of cognates (words with a common origin) traceable to Proto-Austronesian (PAn) varies among language subgroups distributed across the island. Interestingly, a positive correlation was found between the percentage of Y chromosome lineages that derive from Austronesian (as opposed to aboriginal) ancestors and the retention of PAn cognates. We also find a striking correlation between the percentage of PAn cognates and geographic distance from the site where many Sumbanese believe their ancestors arrived on the island. These language-gene-geography correlations, unprecedented at such a fine scale, imply that historical patterns of social interaction between expanding farmers and resident hunter-gatherers largely explain community-level language evolution on Sumba. We propose a model to explain linguistic and demographic coevolution at fine spatial and temporal scales.

Proceedings Publications

• Levin, A., Hallmark, B., Wegienka, G., Johnson, C. C., Billheimer, D., Wright, A. L., Wright, A. L., Zoratti, E. M., Wright, A. L., Wegienka, G., Stanhope, C., Seroogy, C. M., Ownby, D. R., Ober, C., Nicolae, D. L., Naughton, K. A., Myers, J. B., Miller, R. L., Mendonca, E. A., , Martinez, F. D., et al. (2019). Fine Mapping the 17q12-21 Childhood Onset Asthma Locus in Ethnically Diverse Children in the Multi-Center Environment and Child Health Outcomes (ECHO)-Children’s Respiratory and Environmental Workgroup (CREW) Consortium. In D15. THE BEST OF PEDIATRIC ASTHMA EPIDEMIOLOGY.