scholarly journals CCR5Δ32 in Brazil: Impacts of a European Genetic Variant on a Highly Admixed Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Bruna Kulmann-Leal ◽  
Joel Henrique Ellwanger ◽  
José Artur Bogo Chies
Keyword(s):  
Allele Frequency ◽  
Genetic Variant ◽  
Population Level ◽  
Brazilian Population ◽  
Human Populations ◽  
Ccr5 Expression ◽  
Genetic Traits ◽  
Genetic Components ◽  
Base Pair Deletion ◽  
Admixed Population

The genetic background of Brazilians encompasses Amerindian, African, and European components as a result of the colonization of an already Amerindian inhabited region by Europeans, associated to a massive influx of Africans. Other migratory flows introduced into the Brazilian population genetic components from Asia and the Middle East. Currently, Brazil has a highly admixed population and, therefore, the study of genetic factors in the context of health or disease in Brazil is a challenging and remarkably interesting subject. This phenomenon is exemplified by the genetic variant CCR5Δ32, a 32 base-pair deletion in the CCR5 gene. CCR5Δ32 originated in Europe, but the time of origin as well as the selective pressures that allowed the maintenance of this variant and the establishment of its current frequencies in the different human populations is still a field of debates. Due to its origin, the CCR5Δ32 allele frequency is high in European-derived populations (~10%) and low in Asian and African native human populations. In Brazil, the CCR5Δ32 allele frequency is intermediate (4-6%) and varies on the Brazilian States, depending on the migratory history of each region. CCR5 is a protein that regulates the activity of several immune cells, also acting as the main HIV-1 co-receptor. The CCR5 expression is influenced by CCR5Δ32 genotypes. No CCR5 expression is observed in CCR5Δ32 homozygous individuals. Thus, the CCR5Δ32 has particular effects on different diseases. At the population level, the effect that CCR5Δ32 has on European populations may be different than that observed in highly admixed populations. Besides less evident due to its low frequency in admixed groups, the effect of the CCR5Δ32 variant may be affected by other genetic traits. Understanding the effects of CCR5Δ32 on Brazilians is essential to predict the potential use of pharmacological CCR5 modulators in Brazil. Therefore, this study reviews the impacts of the CCR5Δ32 on the Brazilian population, considering infectious diseases, inflammatory conditions, and cancer. Finally, this article provides a general discussion concerning the impacts of a European-derived variant, the CCR5Δ32, on a highly admixed population.

scholarly journals Expanding the Russian allele frequency reference via cross-laboratory data integration: insights from 6,096 exome samples

2021 ◽  
Author(s):  
Yury A Barbitoff ◽  
Darya N Khmelkova ◽  
Ekaterina A Pomerantseva ◽  
Aleksandr V Slepchenkov ◽  
Nikita A Zubashenko ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Genetic Variant ◽  
Laboratory Data ◽  
Medical Genetics ◽  
Pathogenic Variants ◽  
Healthy Donors ◽  
Tenfold Increase ◽  
Novel Variant ◽  
Specific Allele ◽  
Admixed Population

The frequency of a genetic variant in a population is crucially important for accurate interpretation of known and novel variant effects in medical genetics. Recently, several large allele frequency databases, such as Genome Aggregation Database (gnomAD), have been created to serve as a global reference for such studies. However, frequencies of many rare alleles vary dramatically between populations, and population-specific allele frequency can be more informative than the global one. Many countries and regions (including Russia) remain poorly studied from the genetic perspective. Here, we report the first successful attempt to integrate genetic information between major medical genetic laboratories in Russia. We construct an expanded reference set of genetic variants by analyzing 6,096 exome samples collected in two major Russian cities of Moscow and St. Petersburg. An approximately tenfold increase in sample size compared to previous studies allowed us to identify genetically distinct clusters of individuals within an admixed population of Russia. We show that up to 18 known pathogenic variants are overrepresented in Russia compared to other European countries. We also identify several dozen high-impact variants that are present in healthy donors despite either being annotated as pathogenic in ClinVar or falling within genes associated with autosomal dominant disorders. The constructed database of genetic variant frequencies in Russia has been made available to the medical genetics community through a variant browser available at http://ruseq.ru.

scholarly journals Genomic landscape of human diversity across Madagascar

2017 ◽  
Vol 114 (32) ◽  
pp. E6498-E6506 ◽  
Author(s):  
Denis Pierron ◽  
Margit Heiske ◽  
Harilanto Razafindrazaka ◽  
Ignace Rakoto ◽  
Nelly Rabetokotany ◽  
...  
Keyword(s):  
Genomic Diversity ◽  
Eastern Africa ◽  
Human Populations ◽  
Human Diversity ◽  
Genetic Traits ◽  
Paternal Contribution ◽  
Genome Wide ◽  
Genomic Landscape ◽  
Genome Wide Data ◽  
Admixed Population

Although situated ∼400 km from the east coast of Africa, Madagascar exhibits cultural, linguistic, and genetic traits from both Southeast Asia and Eastern Africa. The settlement history remains contentious; we therefore used a grid-based approach to sample at high resolution the genomic diversity (including maternal lineages, paternal lineages, and genome-wide data) across 257 villages and 2,704 Malagasy individuals. We find a common Bantu and Austronesian descent for all Malagasy individuals with a limited paternal contribution from Europe and the Middle East. Admixture and demographic growth happened recently, suggesting a rapid settlement of Madagascar during the last millennium. However, the distribution of African and Asian ancestry across the island reveals that the admixture was sex biased and happened heterogeneously across Madagascar, suggesting independent colonization of Madagascar from Africa and Asia rather than settlement by an already admixed population. In addition, there are geographic influences on the present genomic diversity, independent of the admixture, showing that a few centuries is sufficient to produce detectable genetic structure in human populations.

scholarly journals Putting RFMix and ADMIXTURE to the test in a complex admixed population

2020 ◽  
Author(s):  
Caitlin Uren ◽  
Eileen G. Hoal ◽  
Marlo Möller
Keyword(s):  
World Wide ◽  
Association Studies ◽  
Structured Populations ◽  
Human Populations ◽  
Computational Tools ◽  
Association Analyses ◽  
Local Ancestry ◽  
Diverse World ◽  
Admixed Population ◽  
Global And Local

Abstract Background Global and local ancestry inference in admixed human populations can be performed using computational tools implementing distinct algorithms. The development and resulting accuracy of these tools has been tested largely on populations with relatively straightforward admixture histories but little is known about how well they perform in more complex admixture scenarios. Results Using simulations, we show that RFMix outperforms ADMIXTURE in determining global ancestry proportions even in a complex 5-way admixed population, in addition to assigning local ancestry with an accuracy of 89%. The ability of RFMix to determine global and local ancestry to a high degree of accuracy, particularly in admixed populations provides the opportunity for more accurate association analyses. Conclusion This study highlights the utility of the extension of computational tools to become more compatible to genetically structured populations, as well as the need to expand the sampling of diverse world-wide populations. This is particularly noteworthy as modern-day societies are becoming increasingly genetically complex and some genetic tools and commonly used ancestral populations are less appropriate. Based on these caveats and the results presented here, we suggest that RFMix be used for both global and local ancestry estimation in world-wide complex admixture scenarios particularly when including these estimates in association studies.

scholarly journals Epidemiological trends in digestive cancers compared to trends in alcohol consumption. Facts from Romania: correlation or coincidence?

2018 ◽  
Vol 91 (4) ◽  
pp. 376-386
Author(s):  
Simona Valean ◽  
Romeo Chira ◽  
Dan Dumitrascu
Keyword(s):  
Alcohol Consumption ◽  
Population Level ◽  
Epidemiological Data ◽  
Epidemiological Studies ◽  
Incidence Rates ◽  
Human Populations ◽  
Causative Relationship ◽  
Consumption Data ◽  
Digestive Cancers ◽  
Epidemiological Trends

Cancer has emerged as the leading cause of death in human populations, according to recent estimations. Epidemiological studies emphasized the role of life style and of environmental factors in promoting the risk for digestive cancers. The contribution of alcohol was highly suspected. Even for digestive cancers with dominant infection etiology, like liver cancer and gastric cancer, the contribution of alcohol should be assessed. At population level there is therefore a need to compare trends in epidemiological data of gastrointestinal cancers and data on alcohol consumption, in order to extrapolate any causative relationship. The purpose of this review was to analyze the time trend of digestive cancers in Romania, in terms of mortality rates (between 1955-2012), and incidence rates (between 2008-2012), in males and females, and to analyze the alcohol consumption data, aiming to find out if there is any association.

scholarly journals Fertility control to mitigate human–wildlife conflicts: a review

2014 ◽  
Vol 41 (1) ◽  
pp. 1 ◽  
Author(s):  
Giovanna Massei ◽  
Dave Cowan
Keyword(s):  
Population Growth ◽  
Wildlife Management ◽  
Population Level ◽  
Fertility Control ◽  
Public Consultation ◽  
Human Populations ◽  
Wildlife Diseases ◽  
Isolated Populations ◽  
Wild Mammals ◽  
Practical Applications

As human populations grow, conflicts with wildlife increase. Concurrently, concerns about the welfare, safety and environmental impacts of conventional lethal methods of wildlife management restrict the options available for conflict mitigation. In parallel, there is increasing interest in using fertility control to manage wildlife. The present review aimed at analysing trends in research on fertility control for wildlife, illustrating developments in fertility-control technologies and delivery methods of fertility-control agents, summarising the conclusions of empirical and theoretical studies of fertility control applied at the population level and offering criteria to guide decisions regarding the suitability of fertility control to mitigate human–wildlife conflicts. The review highlighted a growing interest in fertility control for wildlife, underpinned by increasing numbers of scientific studies. Most current practical applications of fertility control for wild mammals use injectable single-dose immunocontraceptive vaccines mainly aimed at sterilising females, although many of these vaccines are not yet commercially available. One oral avian contraceptive, nicarbazin, is commercially available in some countries. Potential new methods of remote contraceptive delivery include bacterial ghosts, virus-like particles and genetically modified transmissible and non-transmissible organisms, although none of these have yet progressed to field testing. In parallel, new species-specific delivery systems have been developed. The results of population-level studies of fertility control indicated that this approach may increase survival and affect social and spatial behaviour of treated animals, although the effects are species- and context-specific. The present studies suggested that a substantial initial effort is generally required to reduce population growth if fertility control is the sole wildlife management method. However, several empirical and field studies have demonstrated that fertility control, particularly of isolated populations, can be successfully used to limit population growth and reduce human–wildlife conflicts. In parallel, there is growing recognition of the possible synergy between fertility control and disease vaccination to optimise the maintenance of herd immunity in the management of wildlife diseases. The review provides a decision tree that can be used to determine whether fertility control should be employed to resolve specific human–wildlife conflicts. These criteria encompass public consultation, considerations about animal welfare and feasibility, evaluation of population responses, costs and sustainability.

Germline Calr Mutation and Thrombocytosis Presenting with Concomitant BCR-ABL1+ CML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5494-5494 ◽  
Author(s):  
Linda B. Baughn ◽  
Scott Gilles ◽  
Elizabeth L. Courville ◽  
Andrew C. Nelson ◽  
Zohar Sachs
Keyword(s):  
Platelet Count ◽  
Allele Frequency ◽  
Peripheral Blood ◽  
Myeloproliferative Neoplasms ◽  
Germline Mutations ◽  
Myelogenous Leukemia ◽  
Base Pair Deletion ◽  
Exon 9 ◽  
Calr Mutations ◽  
Calr Mutation

Abstract CALR mutations are present in 70-84% of JAK2 wild-type myeloproliferative neoplasms (MPN) and 67% and 88% of essential thrombocytopenia (ET) and primary myelofibrosis (PMF) respectively. Most cases of MPN are apparently sporadic, but 7-11% have evidence of familial predisposition. While germline mutations in ET-associated genes, MPL and JAK2, have been described in hereditary thrombocytosis, germline mutations in CALR have not been described in any setting. Two types of CALR mutations are common in MPN: a 52-base pair deletion (bp) and a 5 bp insertion, both in exon 9. With rare exceptions, CALR mutations are generally mutually exclusive with JAK2 or MPL mutations and have very rarely been reported in conjunction with the BCR-ABL1translocation. Here, we report a patient with a germline CALR mutation, thrombocytosis, and subsequent development of BCR-ABL+ CML. A 67-year-old female with no significant medical history presented with severe abdominal pain and nausea. Peripheral blood analysis revealed a marked leukocytosis composed of 66% neutrophils, 16% myelocytes, 6.5% monocytes, 3.5% basophils, 2.5% promyelocytes, 2.5% metamyelocytes, 1.5% lymphocytes, 1.5% blasts, and no eosinophils. The patient was non-anemic and had a normal platelet count (340,000/mm3). Bone marrow biopsy revealed a hypercellular marrow with myeloid predominant trilineage hematopoiesis and 1-2% blasts with morphology consistent with chronic myelogenous leukemia (CML). Fluorescence in-situ hybridization analysis of peripheral blood identified a BCR-ABL1fusion in 98.5% of interphase cells. After 3 months of standard imatinib therapy, quantitative RT-PCR showed a reduction of BCR-ABL1/ABL1 in the peripheral blood, however platelet count was elevated at 539,000/mm3. Thrombocytosis persisted over 2 years with a maximal platelet count of 584,000/mm3. Given the patient's thrombocytosis, her peripheral blood was subjected to a next generation sequencing of JAK2, MPL, and CALR genes. A 52-bp out-of-frame deletion in exon 9 of the CALR gene was detected (52% allele frequency) in peripheral blood. In addition, the same 52-bp CALR deletion (63% allele frequency) was present at the time of diagnosis and within a buccal specimen (47% allele frequency) when the BCR-ABL1 transcript was 1% in the peripheral blood. Immunostain of the buccal sample was strongly positive for cytokeratin (CK) AE1/AE3 but CD45 was not detected indicating no leukocyte contamination. This case reports the first instance of a germline CALR mutation associated with thrombocytosis and is the fourth report of the co-occurrence of BCR-ABL1 and CALR mutation in a single patient. Evolution to BCR-ABL1+ CML suppressed the CALR-mutant thrombocytosis phenotype, emphasizing the effect of these genes on lineage determination in abnormal myeloid proliferation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Rapid genotyping assays for the 4–base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in Border Collie dogs

2011 ◽  
Vol 24 (1) ◽  
pp. 127-134 ◽  
Author(s):  
Keijiro Mizukami ◽  
Hye-Sook Chang ◽  
Akira Yabuki ◽  
Takuji Kawamichi ◽  
Mohammad A. Hossain ◽  
...  
Keyword(s):  
Real Time ◽  
Allele Frequency ◽  
Base Pair ◽  
Real Time Pcr ◽  
Mutant Allele ◽  
Microchip Electrophoresis ◽  
Pcr Assay ◽  
Abcb1 Gene ◽  
P Glycoprotein ◽  
Base Pair Deletion

P-glycoprotein, encoded by the MDR1 or ABCB1 gene, is an integral component of the blood–brain barrier as an efflux pump for xenobiotics crucial in limiting drug uptake into the central nervous system. Dogs homozygous for a 4–base pair deletion of the canine MDR1 gene show altered expression or function of P-glycoprotein, resulting in neurotoxicosis after administration of the substrate drugs. In the present study, the usefulness of microchip electrophoresis for genotyping assays detecting this deletion mutation was evaluated. Mutagenically separated polymerase chain reaction (MS-PCR) and real-time PCR assays were newly developed and evaluated. Furthermore, a genotyping survey was carried out in a population of Border Collies dogs in Japan to determine the allele frequency in this breed. Microchip electrophoresis showed advantages in detection sensitivity and time saving over other modes of electrophoresis. The MS-PCR assay clearly discriminated all genotypes. Real-time PCR assay was most suitable for a large-scale survey due to its high throughput and rapidity. The genotyping survey demonstrated that the carrier and mutant allele frequencies were 0.49% and 0.25%, respectively, suggesting that the mutant allele frequency in Border Collies is markedly low compared to that in the susceptible dog breeds such as rough and smooth Collies.

scholarly journals 3.5KJPNv2, An allele frequency panel of 3,552 Japanese Individuals

2019 ◽  
Author(s):  
Shu Tadaka ◽  
Fumiki Katsuoka ◽  
Masao Ueki ◽  
Kaname Kojima ◽  
Satoshi Makino ◽  
...  
Keyword(s):  
Allele Frequency ◽  
X Chromosome ◽  
Japanese Population ◽  
Population Level ◽  
Genetic Variations ◽  
Genomic Information ◽  
Personalized Healthcare ◽  
Individual Level ◽  
Link Type

AbstractThe first step towards realizing personalized healthcare is to catalog the genetic variations in a population. Since the dissemination of individual-level genomic information is strictly controlled, it will be useful to construct population-level allele frequency panels and to provide them through easy-to-use interfaces.In the Tohoku Medical Megabank Project, we have sequenced nearly 4,000 individuals from a Japanese population, and constructed an allele frequency panel of 3,552 individuals after removing related samples. The panel is called the 3.5KJPNv2. It was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. Our database is the first largescale panel providing the frequencies of variants present on the X chromosome and on the mitochondria in the Japanese population. All the data are available on our original database at https://jmorp.megabank.tohoku.ac.jp.

scholarly journals The genomic signatures of natural selection in admixed human populations

2021 ◽  
Author(s):  
Sebastian Cuadros-Espinoza ◽  
Guillaume Laval ◽  
Lluís Quintana-Murci ◽  
Etienne Patin
Keyword(s):  
Natural Selection ◽  
Human Populations ◽  
Genomic Signatures ◽  
Local Environments ◽  
Admixed Population ◽  
Resistance To Infection ◽  
Source Populations ◽  
Neutral Mutations ◽  
New Evidence

Admixture has been a pervasive phenomenon in human history, shaping extensively the patterns of population genetic diversity. There is increasing evidence to suggest that admixture can also facilitate genetic adaptation to local environments, i.e., admixed populations acquire beneficial mutations from source populations, a process that we refer to as adaptive admixture. However, the role of adaptive admixture in human evolution and the power to detect it are poorly characterized. Here, we use extensive computer simulations to evaluate the power of several neutrality statistics to detect natural selection in the admixed population, accounting for background selection and assuming different admixture scenarios. We show that two statistics based on admixture proportions, F_adm and LAD, show high power to detect mutations that are beneficial in the admixed population, whereas iHS and F_ST falsely detect neutral mutations that have been selected in the source populations only. By combining F_adm and LAD into a single statistic, we scanned the genomes of 15 worldwide, admixed populations for signatures of adaptive admixture. We confirm that lactase persistence and resistance to malaria have been under adaptive admixture in West Africa and in Madagascar, North Africa and South Asia, respectively. Our approach also uncovers new cases of adaptive admixture, including the APOL1 / MYH9 locus in the Fulani nomads and PKN2 in East Indonesians, involved in resistance to infection and metabolism, respectively. Collectively, our study provides new evidence that adaptive admixture has occurred in multiple human populations, whose genetic history is characterized by periods of isolation and spatial expansions resulting in increased gene flow.

scholarly journals Total predicted MHC-I epitope load is inversely associated with population mortality from SARS-COV-2

2020 ◽  
Author(s):  
Eric A. Wilson ◽  
Gabrielle Hirneise ◽  
Abhishek Singharoy ◽  
Karen S. Anderson
Keyword(s):  
Mortality Rate ◽  
Binding Capacity ◽  
Peptide Binding ◽  
Inverse Correlation ◽  
Population Level ◽  
Prediction Algorithm ◽  
Human Populations ◽  
Mhc I ◽  
Cell Immunity ◽  
Population Mortality

AbstractPolymorphisms in MHC-I protein sequences across human populations significantly impacts viral peptide binding capacity and thus alters T cell immunity to infection. Consequently, allelic variants of the MHC-I protein have been found to be associated with patient outcome to various viral infections, including SARS-CoV. In the present study, we assess the relationship between observed SARS-CoV-2 population mortality and the predicted viral binding capacities of 52 common MHC-I alleles. Potential SARS-CoV-2 MHC-I peptides were identified using a consensus MHC-I binding and presentation prediction algorithm, called EnsembleMHC. Starting with nearly 3.5 million candidates, we resolved a few hundred high-confidence MHC-I peptides. By weighing individual MHC allele SARS-CoV-2 binding capacity by population frequency in 23 countries, we discover a strong inverse correlation between the predicted population SARS-CoV-2 peptide binding capacity and observed mortality rate. Our computations reveal that peptides derived from the structural proteins of the virus produces a stronger association with observed mortality rate, highlighting the importance of S, N, M, E proteins in driving productive immune responses. These results bring to light how molecular changes in the MHC-I proteins may affect population-level outcomes of viral infection.

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