Ancestral Allele Research Articles

Two-dimensional site frequency spectrum for detecting, classifying and dating incomplete selective sweeps

The two-dimensional site frequency spectrum (2D SFS) was investigated to describe the intra-allelic variability (IAV) maintained within a derived allele (D) group that has undergone an incomplete selective sweep against an ancestral allele group. We observed that recombination certainly muddles the ancestral relationships of allelic lineages between the two allele groups; however, the 2D SFS reveals intriguing signatures of recombination as well as the genealogical structure of the D group, particularly the size of a mutation and the time to the most recent common ancestor (TMRCA). Coalescent simulations were performed to achieve powerful and robust 2D SFS-based statistics with special reference to accurate evaluation of IAV, significance of recombination effects, and distinction between hard and soft selective sweeps. These studies were extended to a case wherein an incomplete selective sweep is no longer in progress and ceased in the recent past. The 2D SFS-based method was applied to 100 intronic linkage disequilibrium regions randomly chosen from the East Asian population of modern humans to examine the P value distributions of the summary statistics under the null hypothesis of neutrality in a nonequilibrium demographic model. We argue that about 96% of intronic variants are non-adaptive with a 10% false discovery rate. Furthermore, this method was applied to six genomic regions in Eurasian populations that were claimed to have experienced recent selective sweeps. We found that two of these genomic regions did not have significant signals of selective sweeps, but the remaining four had undergone hard and soft sweeps and were dated, in terms of TMRCA, after the major out-of-Africa dispersal of modern humans.

Phylogenetic Origin of Primary and Secondary Metabolic Pathway Genes Revealed by C. maxima and C. reticulata Diagnostic SNPs.

Modern cultivated Citrus species and varieties result from interspecific hybridization between four ancestral taxa. Among them, Citrus maxima and Citrus reticulata, closely associated with the pummelo and mandarin horticultural groups, respectively, were particularly important as the progenitors of sour and sweet oranges (Citrus aurantium and Citrus sinensis), grapefruits (Citrus paradisi), and hybrid types resulting from modern breeding programs (tangors, tangelos, and orangelos). The differentiation between the four ancestral taxa and the phylogenomic structure of modern varieties widely drive the phenotypic diversity’s organization. In particular, strong phenotypic differences exist in the coloration and sweetness and represent important criteria for breeders. In this context, focusing on the genes of the sugar, carotenoid, and chlorophyll biosynthesis pathways, the aim of this work was to develop a set of diagnostic single-nucleotide polymorphism (SNP) markers to distinguish the ancestral haplotypes of C. maxima and C. reticulata and to provide information at the intraspecific diversity level (within C. reticulata or C. maxima). In silico analysis allowed the identification of 3,347 SNPs from selected genes. Among them, 1,024 were detected as potential differentiation markers between C. reticulata and C. maxima. A total of 115 SNPs were successfully developed using a competitive PCR technology. Their transferability among all Citrus species and the true citrus genera was very good, with only 0.87% of missing data. The ancestral alleles of the SNPs were identified, and we validated the usefulness of the developed markers for tracing the ancestral haplotype in large germplasm collections and sexually recombined progeny issued from the C. reticulata/C. maxima admixture gene pool. These markers will pave the way for targeted association studies based on ancestral haplotypes.

Risk assessment of FLT3 and PAX5 variants in B-acute lymphoblastic leukemia: a case–control study in a Pakistani cohort

AIMSB-cell acute lymphoblastic leukemia (B-ALL) is amongst the most prevalent cancers of children in Pakistan. Genetic variations in FLT3 are associated with auto-phosphorylation of kinase domain that leads to increased proliferation of blast cells. Paired box family of transcription factor (PAX5) plays a critical role in commitment and differentiation of B-cells. Variations in PAX5 are associated with the risk of B-ALL. We aimed to analyze the association of FLT3 and PAX5 polymorphisms with B cell leukemia in Pakistani cohort.METHODSWe collected 155 B-ALL subject and 155 control blood samples. For analysis, genotyping was done by tetra ARMS-PCR. SPSS was used to check the association of demographic factors of SNPs present in the population with the risk of B-ALL.RESULTSRisk allele frequency A at locus 13q12.2 (rs35958982, FLT3) was conspicuous and showed positive association (OR = 2.30, CI [1.20–4.50], P = 0.005) but genotype frequency (OR = 3.67, CI [0.75–18.10], P = 0.088) failed to show any association with the disease. At locus 9p13.2 (rs3780135, PAX5), the risk allele frequency was significantly higher in B-ALL subjects than ancestral allele frequency (OR = 2.17, CI [1.37–3.43], P = 0.000). Genotype frequency analysis of rs3780135 polymorphism exhibited the protective effect (OR = 0.55, CI [0.72–1.83], P = 0.029). At locus 13q12.2 (rs12430881, FLT3), the minor allele frequency G (OR = 1.15, CI [1.37–3.43], P = 0.043) and genotype frequency (OR = 2.52, P = 0.006) reached significance as showed p < 0.05.CONCLUSIONIn the present study, a strong risk of B-cell acute lymphoblastic leukemia was associated with rs35958982 and rs12430881 polymorphisms. However, rs3780135 polymorphism showed the protective effect. Additionally, other demographic factors like family history, smoking and consanguinity were also found to be important in risk assessment. We anticipate that the information from genetic variations in this study can aid in therapeutic approach in the future.

Environmental Programming of Adult Foraging Behavior in C.elegans.

Foraging strategies should be tuned to the expected distribution of resources in the environment. Tuning can occur over generations and lead to genetic differences in innate foraging behavior or over shorter timescales within an individual's lifespan. Both genetically encoded and experience-based strategies are implemented by neural circuits that respond to environmental cues and track internal states. Caenorhabditis elegans exhibit both between-strain genetic differences and within-strain plasticity in foraging. In individuals, changes in foraging are usually short term and based on recent experience. Here, we tested whether developmental experience could permanently alter foraging. We found that, in most wild strains, early-life starvation led to "cautious" foraging strategies, in which exploration is reduced, and these behavioral changes are associated with altered dynamics in a locomotory circuit. Possessing either the derived (domestication-associated) or ancestral allele of the neuroglobin glb-5 determines foraging plasticity. Overall, we show that C.elegans exhibit adaptive developmental plasticity that affects multiple aspects of foraging behavior and leads to changes in a core navigation circuit and that innate foraging traits and plasticity in those traits are genetically separable. VIDEO ABSTRACT.

Illuminating the Role of Vpr in HIV Infection of Myeloid Cells.

Vpr is a 14 kDa accessory protein conserved amongst extant primate lentiviruses that is required for virus replication in vivo. Although many functions have been attributed to Vpr, its primary role, and the function under selective pressure in vivo, remains elusive. The minimal importance of Vpr in infection of activated CD4+ T cells in vitro suggests that its major importance lies in overcoming restriction to virus replication in non-cycling myeloid cell populations, such as macrophages and dendritic cells. HIV-1 replication is attenuated in the absence of Vpr in myeloid cells such as monocyte-derived dendritic cells (MDDCs) and macrophages, and is correlated with the ability of Vpr to overcome a post-integration transcriptional defect in these cells. Intriguingly, recent identification of the human hub silencing (HUSH) complex as a target for DCAFCRL4-mediated degradation by numerous ancestral SIV Vpr alleles, and the Vpr paralog Vpx, signifies the potential function of HIV-1 Vpr to alter yet-to-be identified chromatin remodeling complexes and prevent host-mediated transcriptional repression of both invading viral genomes and pro-inflammatory responses. Myeloid cells constitute an important bridge between innate and adaptive immune responses to invading pathogens. Here, we seek to illustrate the numerous means by which Vpr manipulates the myeloid cellular environment and facilitates virus replication, myeloid cell-dependent HIV transmission, and systemic virus dissemination.

Abstract 4565: The functional role of atypical chemokine receptor 1 in immune cell regulation of breast cancer

Abstract Breast cancer (BC) is a heterogeneous disease that leads to varied molecular subtypes and distinct clinical outcomes. Tumor heterogeneity, which is in part influenced by genetic ancestry, contributes to racial disparities in BC. This disparity has persisted for over 30 years, despite improvements in detection, screening, and treatment methods. When investigating race-specific differences in the breast tumor microenvironment (TME), we believe that chemokine receptors, such as atypical chemokine receptor 1 (ACKR1/DARC), play an integral role in regulating chemokine and immune cell migration in circulation and the TME, ultimately influencing tumor progression. ACKR1/DARC specifically plays a role in ancestry-related differences in BC due to an African-specific ancestral allele (“Duffy-null” mutation) that is fixed in Sub-Saharan African populations, and present in 60-70% of African-Americans. Those that harbor the mutation do not express ACKR1/DARC on erythrocytes, ultimately affecting immune cell migration in these populations only. To better understand the effects of this variant in circulation and the TME, we performed immunohistochemistry (IHC) on breast tumors from a cohort of patients with matched blood samples. From our IHC analysis, we quantified levels of ACKR1/DARC, in addition to levels of target pro-inflammatory chemokines, and distinct immune populations of T-cells and macrophages. In addition, individuals were genotyped to determine Duffy-null status, and a correlative Luminex multiplex assay was performed on patient plasma to determine concentrations of pro-inflammatory chemokines in circulation. We determined that those with low expression of ACKR1/DARC in tumors exhibited a unique signature of immune cell infiltrates that would encourage a more aggressive TME. In addition, we observed variable levels of circulating chemokines, where those with the Duffy-null mutation exhibited significantly decreased levels of CCL2. Overall, our analyses support the hypothesis that tumor-specific DARC/ACKR1 plays a vital role in immune cell regulation in women with BC. Citation Format: Brittany D. Jenkins, Rachel Martini, Kevin Gardner, Michele Monteil, Dorrah Deeb, Lisa Newman, Melissa Davis. The functional role of atypical chemokine receptor 1 in immune cell regulation of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4565.

Wxlv, the Ancestral Allele of Rice Waxy Gene

In rice grains, the Waxy (Wx) gene is responsible for the synthesis of amylose, the most important determinant for eating and cooking quality. The effects of several Wx alleles on amylose content and the taste of cooked rice have been elucidated. However, the relationship between artificial selection and the evolution of various Wx alleles as well as their distribution remain unclear. Here we report the identification of an ancestral allele, Wxlv, which dramatically affects the mouthfeel of rice grains by modulating the size of amylose molecules. We demonstrated that Wxlv originated directly from wild rice, and the three major Wx alleles in cultivated rice (Wxb, Wxa, and Wxin) differentiated after the substitution of one base pair at the functional sites. These data indicate that the Wxlv allele played an important role in artificial selection and domestication. The findings also shed light on the evolution of various Wx alleles, which have greatly contributed to improving the eating and cooking quality of rice.

The Domestic BCO2 Allele Buffers Low-Carotenoid Diets in Chickens: Possible Fitness Increase Through Species Hybridization.

Domestic animals are adapted to conditions vastly different from those of their wild ancestors, and this is particularly true for their diets. The most numerous of all domestic species, the chicken, originated from the Red Junglefowl (RJF), a native of subtropical forests in Southeast Asia. Surprisingly however, in domestic chicken breeds, a common haplotype of the β-carotene oxygenase 2 (BCO2) gene, which is involved in carotenoid metabolism, is introgressed from a related species, the Gray Junglefowl, and has been under strong selective pressure during domestication. This suggests that a hybridization event may have conferred a fitness advantage on chickens carrying the derived allele. To investigate the possible biological function of the introgressed BCO2 allele in chicken, we introgressed the ancestral BCO2 allele into domestic White Leghorn chickens. We measured gene expression as well as carotenoid accumulation in skin and eggs of chickens carrying either the ancestral or the derived BCO2 allele. The derived haplotype was associated with down-regulation of BCO2 in skin, muscle, and adipose tissue, but not in liver or duodenum, indicating that carotenoid accumulation occurred in the tissues with reduced gene expression. Most importantly, we found that hens with the derived BCO2 genotype were capable of allocating stored carotenoids to their eggs, suggesting a functional benefit through buffering any shortage in the diet during egg production. Nevertheless, it is of interest that loss of function mutations in BCO2 gene are prevalent in other domesticates including cows, rabbits, and sheep, and, given the importance of carotenoids in development, reproduction, and immunity, it is possible that derived BCO2 alleles may provide a general mechanism in multiple domestic species to deal with higher demand for carotenoids in an environment with carotenoid shortage in the diet.

A missense mutation (p.Tyr452Cys) in the CAD gene compromises reproductive success in French Normande cattle

We scanned the genome of 77,815 Normande cattle with different Illumina SNP chips (Illumina Inc., San Diego, CA) to map recessive embryonic lethal mutations using homozygous haplotype deficiency. We detected 2 novel haplotypes on chromosomes 11 and 24 but did not confirm 6 previously reported haplotypes. The one on chromosome 11 showed a marked reduction in conception rates and moderate decrease in nonreturn rate in at-risk versus control mating, supporting late embryonic mortality. After fine mapping and analyzing whole-genome sequences, we prioritized a missense mutation in CAD (g.72399397T>C; p.Tyr452Cys)-a gene encoding a protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) essential for de novo pyrimidine biosynthesis-as a candidate causal variant. This transition mutation replaces a tyrosine residue, which is perfectly conserved among living organisms, with a cysteine residue in the carbamoyl-phosphate synthetase 2 domain of the protein. A single animal was confirmed to be homozygous for the mutation based on Sanger sequencing. However, large-scale genotyping of the candidate variant with the Illumina EuroG10k BeadChip revealed an absence of live homozygotes in a panel of 33,323 Normande animals and an absence of carriers in 348,593 animals from 19 other cattle breeds. These results support recessive embryonic lethality with nearly complete penetrance, as was previously reported in CAD mutants in several eukaryote species. The only homozygous cow had extremely poor udder conformation, suggesting a potential role of CAD in udder development, but no effect was detected when comparing daughter yield deviations of 250 heterozygous bulls with that of 2,912 homozygotes for the ancestral allele. Together, our results showed the importance of large-scale screening for homozygous haplotype deficiency with hundreds of thousands of animals, validating results with an independent data set, and considering unexpected live homozygotes, to avoid both false-positive and false-negative discoveries. These discoveries will be used primarily in mating decisions to avoid at-risk mating. In addition, we recommend including CAD in the breeding objectives of Normande cattle.

Human low‐affinity IgG receptor FcγRIIA polymorphism H131R associates with subclinical atherosclerosis and increased platelet activity in systemic lupus erythematosus

Essentials Systemic lupus erythematosus (SLE) patients are at increased risk for premature CVD. Platelet activity, vascular dysfunction and carotid artery plaque are associated with FcγRIIA genotype in SLE. FcγRIIA genotype was not associated with platelet activity or carotid plaque in healthy controls. FcγRIIA represents a link that connects platelet activity, vascular health and CVD in SLE. SUMMARY: Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with an elevated risk of premature cardiovascular disease. Platelets express receptors contributing to inflammation and immunity, including FcγRIIA, the low affinity receptor of the Fc portion of IgG antibodies. The variation at a single amino acid substitution, H131R, in the extracellular binding domain alters the affinity for IgG, which may account for individual variation in platelet activity and platelet-mediated disease. Objectives This study was performed to investigate the association between FcγRIIA genotype, preclinical atherosclerosis, platelet reactivity and vascular health. Methods FcγRIIA was genotyped in 80 SLE patients and 30 healthy controls. Carotid ultrasound plaque, soluble E-selectin and platelet aggregability were evaluated in SLE and matched controls. Results Carotid plaque was significantly more prevalent in SLE patients carrying a variant allele compared to those with a homozygous ancestral allele (58% vs. 25%, P=0.04). In contrast, prevalent carotid plaque was not associated with genotype in controls. Consistently, SLE variant FcγRIIA carriers vs. ancestral allele carriers had a significant increase in the levels of soluble E-selectin, which was not observed in controls. Monocyte and leukocyte-platelet aggregation and platelet aggregation in response to submaximal agonist stimulation were significantly elevated in SLE patients with the variant vs. ancestral genotype. Conclusions Carotid ultrasound plaque, soluble E-selectin levels and platelet activity were more frequently prevalent in SLE patients carrying variant FcγRIIA. The interplay between FcγRIIA-mediated platelet activation and endothelial cells might represent a mechanism underlying the pathogenesis of cardiovascular disease in SLE patients.

The Crohn's disease associated SNP rs6651252 impacts MYC gene expression in human colonic epithelial cells.

Crohn’s disease (CD) is a debilitating inflammatory bowel disease (IBD) that arises from chronic inflammation in the gastrointestinal tract. Genome-wide association studies (GWAS) have identified over 200 single nucleotide polymorphisms (SNPs) that are associated with a predisposition for developing IBD. For the majority, the causal variant and target genes affected are unknown. Here, we investigated the CD-associated SNP rs6651252 that maps to a gene desert region on chromosome 8. We demonstrate that rs6651252 resides within a Wnt responsive DNA enhancer element (WRE) and that the disease associated allele augments binding of the TCF7L2 transcription factor to this region. Using CRISPR/Cas9 directed gene editing and epigenetic modulation, we find that the rs6651252 enhancer regulates expression of the c-MYC proto-oncogene (MYC). Furthermore, we found MYC transcript levels are elevated in patient-derived colonic segments harboring the disease-associated allele in comparison to those containing the ancestral allele. These results suggest that Wnt/MYC signaling contributes to CD pathogenesis and that patients harboring the disease-associated allele may benefit from therapies that target MYC or MYC-regulated genes.

The phylogeny of 48 alleles, experimentally verified at 21\xa0kb, and its application to clinical allele detection

BackgroundSequence information generated from next generation sequencing is often computationally phased using haplotype-phasing algorithms. Utilizing experimentally derived allele or haplotype information improves this prediction, as routinely used in HLA typing. We recently established a large dataset of long ERMAP alleles, which code for protein variants in the Scianna blood group system. We propose the phylogeny of this set of 48 alleles and identify evolutionary steps to derive the observed alleles.MethodsThe nucleotide sequence of > 21 kb each was used for all physically confirmed 48 ERMAP alleles that we previously published. Full-length sequences were aligned and variant sites were extracted manually. The Bayesian coalescent algorithm implemented in BEAST v1.8.3 was used to estimate a coalescent phylogeny for these variants and the allelic ancestral states at the internal nodes of the phylogeny.ResultsThe phylogenetic analysis allowed us to identify the evolutionary relationships among the 48 ERMAP alleles, predict 4243 potential ancestral alleles and calculate a posterior probability for each of these unobserved alleles. Some of them coincide with observed alleles that are extant in the population.ConclusionsOur proposed strategy places known alleles in a phylogenetic framework, allowing us to describe as-yet-undiscovered alleles. In this new approach, which relies heavily on the accuracy of the alleles used for the phylogenetic analysis, an expanded set of predicted alleles can be used to infer alleles when large genotype data are analyzed, as typically generated by high-throughput sequencing. The alleles identified by studies like ours may be utilized in designing of microarray technologies, imputing of genotypes and mapping of next generation sequencing data.

BST1 rs4698412 allelic variant increases the risk of gait or balance deficits in patients with Parkinson's disease.

SummaryAimsWe aimed to explore effects of bone marrow stromal cell antigen‐1 (BST1) rs4698412 allelic variant on brain activation and associative clinical symptoms in Parkinson’s disease (PD).MethodsA total of 49 PD patients and 47 healthy control (HC) subjects were recruited for clinical evaluations, blood samples collection for genotypes, and resting‐state functional MRI (rs‐fMRI) scans. Based on BST1 rs4698412 allelic variant (G → A), participants were further divided into 18 PD‐GG, 31 PD‐GA/AA, 20 HC‐GG, and 27 HC‐GA/AA carriers, which respectively indicated subjects carrying ancestral or risk allele in that locus in PD or HC. Two‐way analysis of covariance (ANCOVA) was applied to investigate main effects and interactions between PD and BST1 rs4698412 allelic variant on brain function via amplitude of low‐frequency fluctuations (ALFF). Spearman’s correlations were then utilized to detect associations between interactive brain regions and clinical symptoms.ResultsCompared to HC subjects, PD patients exhibited increased ALFF values in left cerebellum_8 and cerebellum_9. Significant interaction was in right lingual gyrus, where there were the lowest ALFF values and ALFF values were only negatively associated with Timed Up and Go (TUG) test time in PD‐GA/AA subgroup.ConclusionBST1 rs4698412‐modulated lingual gyrus functional alterations could be related to gait and balance dysfunction in PD.

Analysis of the low functional allele 7(TA) of the UGT1A1 gene in healthy population in the Western region of Ukraine

Gilbert's syndrome, GS (non-hemolytic anemia) is a pathological condition caused by enzyme (uridine diphosphate glucuronosyltransferase) failure to degrade bilirubin because of UGT1A1 gene mutations, which generally are TA insertions in the promoter region. Disorder entails constantly high level of bilirubin in the blood, and its toxicity causes symptoms manifestation. The pathology doesn’t require therapy, but it increases the risk of concomitant disorders and requires a special approach when prescribing therapy with drugs. The frequency of Gilbert's syndrome ranges from 0.6% to 43% worldwide, the frequency in Ukraine is not known exactly. Thus, the aim of the work was, based on analysis of published data, to study the world distribution of Gilbert's syndrome risk alleles, to find their associations with other pathological conditions, and to establish the frequency of the low-functional allele and various genotypes in TA [A(TA)6TAA] locus of UGT1A1 gene among residents of the Western region of Ukraine. Blood samples from 130 healthy residents of the Western region of Ukraine were collected, DNA samples were isolated by salting method. DNA amplification was performed by PCR followed by 10% PAG analysis and HRM analysis (high resolution melting). The pathogenic allele frequency was 34.3%, the frequency of the ancestral allele was 65.7%. The frequency of the mutant homozygous genotype was 14.6%, which coincides with published data. The frequency of the mutant genotype equals 8–18% for European countries, so our data coincide with results of population studies of European countries residents. It should be noted that these 14.6% of population are of high risk of concomitant disorders, such as colorectal cancer in men, breast cancer in women, diseases of the gastrointestinal tract, biliary calculus and formation of kidney stones. Thus, it is advisable to analyze 7(TA) alleles (risk alleles for Gilbert's syndrome) of the UGT1A1 gene in patients with hyperbilirubinemia of undetermined origin to diagnose Gilbert's syndrome.

Dilemmas and challenges in apolipoprotein L1 nephropathy research.

The purpose of this mini-review is to highlight some unresolved questions and controversies in the evolving story of apolipoprotein L1 (APOL1) nephropathy. We highlight studies that introduce complexity in unraveling the mechanisms whereby APOL1 risk variant alleles cause disease. These include studies which support a possible protective role for the APOL1 GO nonrisk ancestral allele, and studies which explore the initiating events that may trigger other downstream pathways mediating APOL1 cellular injury. We also review studies that reconcile the perplexing findings regarding APOL1 anionic or cationic conductance, and pH dependency, and also studies that attempt to characterize the 3-dimensional structure of APOL1 C-terminal in APOL1 variants, as well as that of the serum resistance-associated protein. We also attempt to convey new insights from in-vivo and in-vitro models, including studies that do not support the differential toxicity of APOL1 renal risk variants and recapitulate the clinical variability of individuals at genotypic risk. Along with major progress that had been achieved in the field of APOL1 nephropathy, controversies and enigmatic issues persist. It remains to be determined which of the pathways which have been demonstrated to mediate cell injury by ectopically expressed APOL1 risk variants in cellular and organismal models are relevant to human disease and can pave the way to potential therapy.

A game of hide and seq: Identification of parallel Y-STR evolution in deep-rooting pedigrees.

Short tandem repeats on the Y-chromosome (Y-STRs) are common DNA polymorphisms useful for genetic genealogy, population and evolutionary genetics, human genetics, pathology and forensic sciences. It is important to identify all Y-STR variants and to have knowledge of Y-STR mutation rates in order to correctly estimate the time to the most recent common ancestor (tMRCA) between paternally related individuals. When capillary electrophoresis (CE) is performed to analyze genealogical pairs, Y-STR sequence variations remain hidden when the number of repeats is identical. These hidden variations could be due to parallel Y-STR changes or modifications (PM) that occur independently in different lineages leading to alleles with identical number of repeats. In this study, we detect for the first time twelve PM by analyzing 133 males (960 meiosis) in extended deep-rooting family pedigrees on 42 Y-STRs. These PM were observed in nine Y-STR loci with mutation rates of at least 5.94 × 10-3 per generation. Sequencing analysis made it possible to distinguish insertions/deletions in different repeat regions revealing the presence of two unique changes in three PM on rapidly mutating and complex Y-STRs DYS724-ab and DYS518. Sequencing unraveled more information concerning the identity of alleles, and increased allelic discrimination possibilities which is of great importance in population genetics and forensic analysis. Limiting the analysis to CE could lead to wrong ancestral allele assumptions, to false negative interpretations and to tMRCA underestimations. These observations highlight the importance and added value of sequencing analysis and suggest a shift in genotyping methods from CE to next generation sequencing.

Signatures of Selection in Admixed Dairy Cattle in Tanzania.

Multiple studies have investigated selection signatures in domestic cattle and other species. However, there is a dearth of information about the response to selection in genomes of highly admixed crossbred cattle in relation to production and adaptation to tropical environments. In this study, we evaluated 839 admixed crossbred cows sampled from two major dairy regions in Tanzania namely Rungwe and Lushoto districts, in order to understand their genetic architecture and detect genomic regions showing preferential selection. Animals were genotyped at 150,000 SNP loci using the Geneseek Genomic Profiler (GGP) High Density (HD) SNP array. Population structure analysis showed a large within-population genetic diversity in the study animals with a high degree of variation in admixture ranging between 7 and 100% taurine genes (dairyness) of mostly Holstein and Friesian ancestry. We explored evidence of selection signatures using three statistical methods (iHS, XP-EHH, and pcadapt). Selection signature analysis identified 108 candidate selection regions in the study population. Annotation of these regions yielded interesting genes potentially under strong positive selection including ABCG2, ABCC2, XKR4, LYN, TGS1, TOX, HERC6, KIT, PLAG1, CHCHD7, NCAPG, and LCORL that are involved in multiple biological pathways underlying production and adaptation processes. Several candidate selection regions showed an excess of African taurine ancestral allele dosage. Our results provide further useful insight into potential selective sweeps in the genome of admixed cattle with possible adaptive and productive importance. Further investigations will be necessary to better characterize these candidate regions with respect to their functional significance to tropical adaptations for dairy cattle.

Unfavorable variants of folate metabolism genes in patients with acute coronary syndrome in non-obstructive coronary atherosclerosis

Aim . To study the occurrence of allelic variants of folate cycle enzymes’ genes, which are unfavorable with respect to the risk of thrombophilia, to analyze the serum level of homocysteine, and to assess their impact on the development of acute coronary syndrome (ACS) in non-obstructive coronary atherosclerosis (NOCA). Material and methods . The material for the study was the results of a non- randomized, open, controlled conduct research, NCT02655718' conducted in 2015-2016 in the emergency cardiology department. The sampling included patients older than 18 years with ACS and NOCA, confirmed by invasive coronary angiography (ICAG). Patients who had previously undergone coronary artery revascularization were excluded from the study. We analyzed four polymorphic genotypes of folate cycle enzyme genes of included patients: methylene-tetra- hydro-folate-reductase MTHFR (677 C>T, 1298 A>C), methionine synthetase MTR (2756 A>G), methionine synthetase reductase MTRR (66 A>G). Determination of genotypes was performed using the methods of polymerase chain reaction and the use of a set of reagents produced by OOO “DNK-Tekhnologiya”. The level of homocysteine was determined by the enzyme immunoenzyme technique using Axis (UK) set of instruments for diagnosis and standards methods. Results . In 2015-2016 913 patients with ACS were hospitalized in emergency cardiology department; 44 (4.8%) were patients with NOKA. The mean age was 54±11 years (68% men). Mean level of homocysteine in the examined patients was 12,2 (10,8; 13,6) umol/l, in men — 12,4 umol/l (11,5; 13,6), in women — 11,3 umol/l (9,5; 13,2). Hyperhomocisteinemia (HHC) was registered in 8 (18%) individuals. The median level of homocysteine in patients with HHC was 22,8 (17,2; 25). An increase in the ultra-sensitive C-reactive protein and diagnosing of acute myocardial infarction (AMI) were more common in patients with HHC. The level of homocysteine did not differ in patients with various degrees of coronary artery stenosis; it was associated with age, hereditary background, smoking and the carriage of an unfavorable homozygous polymorphic variant of the TT genotype MTHFR gene (677 C>T). The carriage of the unfavorable TT genotype MTHFR (677 C>T) was statistically significantly more common in patients with AMI. The carriage of unfavorable homo- and heterozygous genotypes of the MTHFR gene (677 C>T) in the group without HHC was also detected. The ancestral allele C of the rs1801133 gene was statistically significantly more common in intact coronary arteries. Conclusion . In this study 96,6% of patients with ACS and NOCA were carriers of unfavorable polymorphic variants of folate metabolism genes. The carriage frequency of unfavorable T allele of rs1801133 gene is statistically significantly more common in patients with AMI. The presence of this genotype is associated with the development of HHC, which is equivalent of literature data. However, the presence of the allelic variant of TT MTHFR (677 C>T) did not always lead to the development of HHC. An increase in plasma homocysteine levels is directly proportional to age, hereditary background, smoking, and carriage of the TT rs1801133 genotype. It is also associated with an increased risk of AMI, which confirms previous studies.

Morphological and genetic diversity of Pura Raza Español horse with regard to the coat colour.

Gene mutations influencing melanocytes also impact on physiological and behavioural functions. In this study, we investigated their association with four different coat colours in the Pura Raza Español (PRE) horse using morphological traits and molecular datasets. Four different subpopulations were identified according to individual coat colour: grey, bay, chestnut and black. Coat colour significantly associated with morphological measurements. Observed and expected heterozygosity values were low in grey compared with the other three subpopulations, suggesting the presence of unique ancestral alleles probably arisen by genetic drift and selection mechanism effects. Nei's distance demonstrated a clear division among subpopulations, the grey being the most divergent group. Gene flow estimates were similar, showing the lowest values in grey. Divergence times among subpopulations assessed with the average square distance suggested that grey was the original PRE population which diverged from bay, chestnut and black. Our results also demonstrated a clear morphological differentiation according to coat colour. The close genetic structure of bay and chestnut PRE subpopulations and the clear differences in most morphological traits of grey and chestnut PRE mares would suggest the pleiotropic effect of genomic regions determining coat colour in horses. However, further analysis including genomic information would be necessary to elucidate the mechanisms involved.

Genetic disease risks can be misestimated across global populations

BackgroundAccurate assessment of health disparities requires unbiased knowledge of genetic risks in different populations. Unfortunately, most genome-wide association studies use genotyping arrays and European samples. Here, we integrate whole genome sequence data from global populations, results from thousands of genome-wide association studies (GWAS), and extensive computer simulations to identify how genetic disease risks can be misestimated.ResultsIn contrast to null expectations, we find that risk allele frequencies at known disease loci are significantly different for African populations compared to other continents. Strikingly, ancestral risk alleles are found at 9.51% higher frequency in Africa, and derived risk alleles are found at 5.40% lower frequency in Africa. By simulating GWAS with different study populations, we find that non-African cohorts yield disease associations that have biased allele frequencies and that African cohorts yield disease associations that are relatively free of bias. We also find empirical evidence that genotyping arrays and SNP ascertainment bias contribute to continental differences in risk allele frequencies. Because of these causes, polygenic risk scores can be grossly misestimated for individuals of African descent. Importantly, continental differences in risk allele frequencies are only moderately reduced if GWAS use whole genome sequences and hundreds of thousands of cases and controls. Finally, comparisons between uncorrected and corrected genetic risk scores reveal the benefits of considering whether risk alleles are ancestral or derived.ConclusionsOur results imply that caution must be taken when extrapolating GWAS results from one population to predict disease risks in another population.