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Sequencing DNA derived from archaic bones has enabled genetic comparison of Neanderthals and anatomically modern humans (AMHs), and revealed that they interbred. However, interpreting what genetic differences imply about their phenotypic differences remains challenging. Here, we introduce an approach for identifying divergent gene regulation between archaic hominins, such as Neanderthals, and AMH sequences, and find 766 genes that are likely to have been divergently regulated (DR) by Neanderthal haplotypes that do not remain in AMHs. DR genes include many involved in phenotypes known to differ between Neanderthals and AMHs, such as the structure of the rib cage and supraorbital ridge development. They are also enriched for genes associated with spontaneous abortion, polycystic ovary syndrome, myocardial infarction and melanoma. Phenotypes associated with modern human variation in these genes' regulation in ~23,000 biobank patients further support their involvement in immune and cardiovascular phenotypes. Comparing DR genes between two Neanderthals and a Denisovan revealed divergence in the immune system and in genes associated with skeletal and dental morphology that are consistent with the archaeological record. These results establish differences in gene regulatory architecture between AMHs and archaic hominins, and provide an avenue for exploring phenotypic differences between archaic groups from genomic information alone.
Immunity genes have repeatedly experienced natural selection during mammalian evolution. Galectins are carbohydrate-binding proteins that regulate diverse immune responses, including maternal-fetal immune tolerance in placental pregnancy. Seven human galectins, four conserved across vertebrates and three specific to primates, are involved in placental development. To comprehensively study the molecular evolution of these galectins, both across mammals and within humans, we conducted a series of between- and within-species evolutionary analyses. By examining patterns of sequence evolution between species, we found that primate-specific galectins showed uniformly high substitution rates, whereas two of the four other galectins experienced accelerated evolution in primates. By examining human population genomic variation, we found that galectin genes and variants, including variants previously linked to immune diseases, showed signatures of recent positive selection in specific human populations. By examining one nonsynonymous variant in Galectin-8 previously associated with autoimmune diseases, we further discovered that it is tightly linked to three other nonsynonymous variants; surprisingly, the global frequency of this four-variant haplotype is ∼50%. To begin understanding the impact of this major haplotype on Galectin-8 protein structure, we modeled its 3D protein structure and found that it differed substantially from the reference protein structure. These results suggest that placentally expressed galectins experienced both ancient and more recent selection in a lineage- and population-specific manner. Furthermore, our discovery that the major Galectin-8 haplotype is structurally distinct from and more commonly found than the reference haplotype illustrates the significance of understanding the evolutionary processes that sculpted variants associated with human genetic disease.
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
Novel regulatory elements that enabled expression of pre-existing immune genes in reproductive tissues and novel immune genes with pregnancy-specific roles in eutherians have shaped the evolution of mammalian pregnancy by facilitating the emergence of novel mechanisms for immune regulation over its course. Trade-offs arising from conflicting fitness effects on reproduction and host defenses have further influenced the patterns of genetic variation of these genes. These three mechanisms (novel regulatory elements, novel immune genes, and trade-offs) played a pivotal role in refining the regulation of maternal immune systems during pregnancy in eutherians, likely facilitating the establishment of prolonged direct maternal-fetal contact in eutherians without causing immunological rejection of the genetically distinct fetus.
© 2019 WILEY Periodicals, Inc.
OBJECTIVES - Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis.
DESIGN - Retrospective cohort study.
SETTING - Medical and surgical ICUs at a large tertiary care center.
PATIENTS - Caucasian and African American adults with sepsis.
MEASUREMENTS AND MAIN RESULTS - We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03).
CONCLUSIONS - Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.
INTRODUCTION - HLA class II allele, DRB1*03:01, is the most common genetic risk factor for autoimmune hepatitis (AIH), but other unrecognized HLA related risks exist.
METHODS - We compared the HLA class I (A, B, C) and class II (DR, DQ, DP) typing between patients with well-characterized AIH and healthy controls by high resolution sequencing of the HLA region. Seventy-three patients with AIH and 87 healthy controls were included. Association between HLA alleles and AIH was considered singly and in clusters and adjusted for age, gender, and DRB1*03:01.
RESULTS - DRB1*03:01 was singly associated with AIH among whites (odds ratio [OR]: 3.09, P = 0.002) and carriers of DRB1*03:01 also carried DQA*05:01 and DQB1*02:01. Significant HLA class I alleles were associated with AIH including those belonging to the A03 (OR: 0.4, P = 0.01) and B44 supertype (OR: 0.44, P = 0.03). Further refinement of HLA-A by binding pocket structure revealed that the sequence Y(F/T)AVMENV(H/Q)Y, corresponding to HLA-A alleles A*03:01-02; *31:01; *32:02, was protective for AIH (OR: 0.3, P = 0.002). A protective association also existed for alleles belonging to the HLA-B binding pocket structure Y(H/Y)TVKEISNY (OR: 0.35, P = 0.01), corresponding to HLA-B alleles: B*40:01-02; *41:02; *44:02-03; *45:01; *49:01; *50:01-02. Associations with specific class I alleles belonging to the 8.1 ancestral haplotype (HLA-A*01:01, HLA-B*08:01, HLA-C*07:01) were not significant when considered jointly with DRB1*03:01 and reported protective class I alleles.
DISCUSSION - Our study identified novel supertypes and HLA-A and B peptide binding structures protective against AIH. Further risk assessment of class I molecules remains important in AIH as they are key mediators of adaptive immunity.
BACKGROUND & AIMS - Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. In this study we aimed to describe the presenting features and outcomes of patients with terbinafine hepatotoxicity and to investigate the role of human leukocyte antigen (HLA)-A*33:01.
METHODS - Consecutive high causality cases of terbinafine hepatotoxicity enrolled into the Drug Induced Liver Injury Network were reviewed. DNA samples underwent high-resolution confirmatory HLA sequencing using the Ilumina MiSeq platform.
RESULTS - All 15 patients with terbinafine hepatotoxicity were more than 40 years old (median = 57 years), 53% were female and the median latency to onset was 38 days (range 24 to 114 days). At the onset of drug-induced liver injury, 80% were jaundiced, median serum alanine aminotransferase was 448 U/L and alkaline phosphatase was 333 U/L. One individual required liver transplantation for acute liver failure during follow-up, and 7 of the 13 (54%) remaining individuals had ongoing liver injury at 6 months, with 4 demonstrating persistently abnormal liver biochemistries at month 24. High-resolution HLA genotyping confirmed that 10 of the 11 (91%) European ancestry participants were carriers of the HLA-A*33:01, B*14:02, C*08:02 haplotype, which has a carrier frequency of 1.6% in European Ancestry population controls. One African American patient was also an HLA-A*33:01 carrier while 2 East Asian patients were carriers of a similar HLA type: A*33:03. Molecular docking studies indicated that terbinafine may interact with HLA-A*33:01 and A*33:03.
CONCLUSIONS - Patients with terbinafine hepatotoxicity most commonly present with a mixed or cholestatic liver injury profile and frequently have residual evidence of chronic cholestatic injury. A strong genetic association of HLA-A*33:01 with terbinafine drug-induced liver injury was confirmed amongst Caucasians.
LAY SUMMARY - A locus in the human leukocyte antigen gene (HLA-A*33:01, B*14:02, C*08:02) was significantly overrepresented in Caucasian and African American patients with liver injury attributed to the antifungal medication, terbinafine. These data along with the molecular docking studies demonstrate that this genetic polymorphism is a plausible risk factor for developing terbinafine hepatotoxicity and could be used in the future to help doctors make a diagnosis more rapidly and confidently.
Copyright © 2018 European Association for the Study of the Liver. All rights reserved.
HIV-associated neurocognitive impairment (NCI) is a term established to capture a wide spectrum of HIV related neurocognitive deficits ranging in severity from asymptomatic to dementia. The genetic underpinnings of this complex phenotype are incompletely understood. Mitochondrial function has long been thought to play a role in neurodegeneration, along with iron metabolism and transport. In this work, we aimed to characterize the interplay of mitochondrial DNA (mtDNA) haplogroup and nuclear genetic associations to NCI phenotypes in the CHARTER cohort, encompassing 1025 individuals of European-descent, African-descent, or admixed Hispanic. We first employed a polygenic modeling approach to investigate the global effect of previous marginally associated nuclear SNPs, and to examine how the polygenic effect of these SNPs is influenced by mtDNA haplogroups. We see evidence of a significant interaction between nuclear SNPs en masse and mtDNA haplogroups within European-descent and African-descent individuals. Subsequently, we performed an analysis of each SNP by mtDNA haplogroup, and detected significant interactions between two nuclear SNPs (rs17160128 and rs12460243) and European haplogroups. These findings, which require validation in larger cohorts, indicate a potential new role for nuclear-mitochondrial DNA interactions in susceptibility to NCI and shed light onto the pathophysiology of this neurocognitive phenotype.
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
Background - Age-related gait speed decline is accelerated in men with human immunodeficiency virus (HIV). Mitochondrial genetic variation is associated with frailty and mortality in the general population and may provide insight into mechanisms of functional decline in people aging with HIV.
Methods - Gait speed was assessed semiannually in the Multicenter AIDS Cohort Study. Mitochondrial DNA (mtDNA) haplogroups were extracted from genome-wide genotyping data, classifying men aged ≥50 years into 5 groups: mtDNA haplogroup H, J, T, Uk, and other. Differences in gait speed by haplogroups were assessed as rate of gait speed decline per year, probability of slow gait speed (<1.0 m/s), and hazard of slow gait using multivariable linear mixed-effects models, mixed-effects logistic regression models, and the Andersen-Gill model, controlling for hepatitis C virus infection, previous AIDS diagnosis, thymidine analogues exposure, education, body composition, smoking, and peripheral neuropathy. Age was further controlled for in the mixed-effects logistic regression models.
Results - A total of 455 HIV-positive white men aged ≥50 years contributed 3283 person-years of follow-up. Among them, 70% had achieved HIV viral suppression. In fully adjusted models, individuals with haplogroup J had more rapid decline in gait speed (adjusted slopes, 0.018 m/s/year vs 0.011 m/s/year, pinteraction = 0.012) and increased risk of developing slow gait (adjusted odds ratio, 2.97; 95% confidence interval, 1.24-7.08) compared to those with other haplogroups.
Conclusions - Among older, HIV-infected men, mtDNA haplogroup J was an independent risk factor for more rapid age-related gait speed decline.
Purpose - We previously demonstrated an association between European mitochondrial haplogroups and proliferative diabetic retinopathy (PDR). The purpose of this study was to determine how the relationship between these haplogroups and both diabetes duration and hyperglycemia, two major risk factors for diabetic retinopathy (DR), affect PDR prevalence.
Methods - Our population consisted of patients with type 2 diabetes with (n = 377) and without (n = 480) DR. A Kruskal-Wallis test was used to compare diabetes duration and hemoglobin A1c (HbA1c) among mitochondrial haplogroups. Logistic regressions were performed to investigate diabetes duration and HbA1c as risk factors for PDR in the context of European mitochondrial haplogroups.
Results - Neither diabetes duration nor HbA1c differed among mitochondrial haplogroups. Among DR patients from haplogroup H, longer diabetes duration and increasing HbA1c were significant risk factors for PDR (P = 0.0001 and P = 0.011, respectively). Neither diabetes duration nor HbA1c was a significant risk factor for PDR in DR patients from haplogroup UK.
Conclusions - European mitochondrial haplogroups modify the effects of diabetes duration and HbA1c on PDR risk in patients with type 2 diabetes. In our patient population, longer diabetes duration and higher HbA1c increased PDR risk in patients from haplogroup H, but did not affect PDR risk in patients from haplogroup UK. This relationship has not been previously demonstrated and may explain, in part, why some patients with nonproliferative DR develop PDR and others do not, despite similar diabetes duration and glycemic control.
Genomic maps of local ancestry identify ancestry transitions - points on a chromosome where recent recombination events in admixed individuals have joined two different ancestral haplotypes. These events bring together alleles that evolved within separate continential populations, providing a unique opportunity to evaluate the joint effect of these alleles on health outcomes. In this work, we evaluate the impact of genetic variants in the context of nearby local ancestry transitions within a sample of nearly 10,000 adults of African ancestry with traits derived from electronic health records. Genetic data was located using the Metabochip, and used to derive local ancestry. We develop a model that captures the effect of both single variants and local ancestry, and use it to identify examples where local ancestry transitions significantly interact with nearby variants to influence metabolic traits. In our most compelling example, we find that the minor allele of rs16890640 occuring on a European background with a downstream local ancestry transition to African ancestry results in significantly lower mean corpuscular hemoglobin and volume. This finding represents a new way of discovering genetic interactions, and is supported by molecular data that suggest changes to local ancestry may impact local chromatin looping.