Adaptive introgression of the beta-globin cluster in two Andean waterfowl

Introgression of beneficial alleles has emerged as an important avenue for genetic adaptation in both plant and animal populations. In vertebrates, adaptation to hypoxic high-altitude environments involves the coordination of multiple molecular and cellular mechanisms, including selection on the hypoxia-inducible factor (HIF) pathway and the blood-O₂ transport protein hemoglobin (Hb). In two Andean duck species, a striking DNA sequence similarity reflecting identity by descent is present across the ~20 kb β-globin cluster including both embryonic (HBE) and adult (HBB) paralogs, though it was yet untested whether this is due to independent parallel evolution or adaptive introgression. In this study, we find that identical amino acid substitutions in the β-globin cluster that increase Hb-O₂ affinity have likely resulted from historical interbreeding between high-altitude populations of two different distantly-related species. We examined the direction of introgression and discovered that the species with a deeper mtDNA divergence that colonized high altitude earlier in history (Anas flavirostris) transferred adaptive genetic variation to the species with a shallower divergence (A. georgica) that likely colonized high altitude more recently possibly following a range shift into a novel environment. As a consequence, the species that received these β-globin variants through hybridization might have adapted to hypoxic conditions in the high-altitude environment more quickly through acquiring beneficial alleles from the standing, hybrid-origin variation, leading to faster evolution.Subject terms: Evolutionary genetics, Evolutionary biology     

Genetic association with boldness and maternal performance in a free-ranging population of grey seals (Halichoerus grypus)

Individual variation in quantitative traits clearly influence many ecological and evolutionary processes. Moderate to high heritability estimates of personality and life-history traits suggest some level of genetic control over these traits. Yet, we know very little of the underlying genetic architecture of phenotypic variation in the wild. In this study, we used a candidate gene approach to investigate the association of genetic variants with repeated measures of boldness and maternal performance traits (weaning mass and lactation duration) collected over an 11- and 28-year period, respectively, in a free-ranging population of grey seals on Sable Island National Park Reserve, Canada. We isolated and re-sequenced five genes: dopamine receptor D4 (DRD4), serotonin transporter (SERT), oxytocin receptor (OXTR), and melanocortin receptors 1 (MC1R) and 5 (MC5R). We discovered single nucleotide polymorphisms (SNPs) in each gene; and, after accounting for loci in linkage disequilibrium and filtering due to missing data, we were able to test for genotype-phenotype relationships at seven loci in three genes (DRD4, SERT, and MC1R). We tested for association between these loci and traits of 180 females having extreme shy-bold phenotypes using mixed-effects models. One locus within SERT was significantly associated with boldness (effect size = 0.189) and a second locus within DRD4 with weaning mass (effect size = 0.232). Altogether, genotypes explained 6.52–13.66% of total trait variation. Our study substantiates SERT and DRD4 as important determinants of behaviour, and provides unique insight into the molecular mechanisms underlying maternal performance variation in a marine predator.Subject terms: Behavioural ecology, Evolutionary genetics, Behavioural genetics, Genetic association study, Quantitative trait     

Identification of 6 gene markers for survival prediction in osteosarcoma cases based on multi-omics analysis

Multiple-omics sequencing information with high-throughput has laid a solid foundation to identify genes associated with cancer prognostic process. Multiomics information study is capable of revealing the cancer occurring and developing system according to several aspects. Currently, the prognosis of osteosarcoma is still poor, so a genetic marker is needed for predicting the clinically related overall survival result. First, Office of Cancer Genomics (OCG Target) provided RNASeq, copy amount variations information, and clinically related follow-up data. Genes associated with prognostic process and genes exhibiting copy amount difference were screened in the training group, and the mentioned genes were integrated for feature selection with least absolute shrinkage and selection operator (Lasso). Eventually, effective biomarkers received the screening process. Lastly, this study built and demonstrated one gene-associated prognosis mode according to the set of the test and gene expression omnibus validation set; 512 prognosis-related genes (P < 0.01), 336 copies of amplified genes (P < 0.05), and 36 copies of deleted genes (P < 0.05) were obtained, and those genes of the mentioned genomic variants display close associations with tumor occurring and developing mechanisms. This study generated 10 genes for candidates through the integration of genomic variant genes as well as prognosis-related genes. Six typical genes (i.e. MYC, CHIC2, CCDC152, LYL1, GPR142, and MMP27) were obtained by Lasso feature selection and stepwise multivariate regression study, many of which are reported to show a relationship to tumor progressing process. The authors conducted Cox regression study for building 6-gene sign, i.e. one single prognosis-related element, in terms of cases carrying osteosarcoma. In addition, the samples were able to be risk stratified in the training group, test set, and externally validating set. The AUC of five-year survival according to the training group and validation set reached over 0.85, with superior predictive performance as opposed to the existing researches. Here, 6-gene sign was built to be new prognosis-related marking elements for assessing osteosarcoma cases’ surviving state.     

Genetic Heterogeneity of Susceptibility Gene in Different Ethnic Populations: Refining Association Study of PTPN22 for Graves’ Disease in a Chinese Han Population

In our previous studies, we presumed subtypes of Graves’ disease (GD) may be caused by different major susceptibility genes or different variants of a single susceptibility gene. However, more evidence is needed to support this hypothesis. Single-nucleotide polymorphism (SNP) rs2476601 in PTPN22 is the susceptibility loci of GD in the European population. However, this polymorphism has not been found in Asian populations. Here, we investigate whether PTPN22 is the susceptibility gene for GD in Chinese population and further determine the susceptibility variant of PTPN22 in GD. We conducted an imputation analysis based on the results of our genome-wide association study (GWAS) in 1,536 GD patients and 1,516 control subjects. Imputation revealed that 255 common SNPs on a linkage disequilibrium (LD) block containing PTPN22 were associated with GD (P<0.05). Nine tagSNPs that captured the 255 common variants were selected to be further genotyped in a large cohort including 4,368 GD patients and 4,350 matched controls. There was no significant difference between the nine tagSNPs (P>0.05) in either the genotype distribution or allelic frequencies between patients and controls in the replication study. Although the combined analysis exhibited a weak association signal (P _combined = 0.003263 for rs3811021), the false positive report probability (FPRP) analysis indicated it was most likely a false positive finding. Our study did not support an association of common SNPs in PTPN22 LD block with GD in Chinese Han population. This suggests that GD in different ethnic population is probably caused by distinct susceptibility genes.     

The effect of PTZ-induced epileptic seizures on hippocampal expression of PSA-NCAM in offspring born to kindled rats

Background

Maternal epileptic seizures during pregnancy can affect the hippocampal neurons in the offspring. The polysialylated neural cell adhesion molecule (PSA-NCAM), which is expressed in the developing central nervous system, may play important roles in neuronal migration, synaptogenesis, and axonal outgrowth. This study was designed to assess the effects of kindling either with or without maternal seizures on hippocampal PSA-NCAM expression in rat offspring.

Methods

Forty timed-pregnant Wistar rats were divided into four groups: A) Kind⁺/Seiz⁺, pregnant kindled (induced two weeks prior to pregnancy) rats that received repeated intraperitoneal (i.p.) pentylenetetrazol, PTZ injections on gestational days (GD) 14-19; B) Kind^-/Seiz⁺, pregnant non-kindled rats that received PTZ injections on GD14-GD19; C) Kind⁺/Seiz^-, pregnant kindled rats that did not receive any PTZ injections; and D) Kind^-/Seiz^-, the sham controls. Following birth, the pups were sacrificed on PD1 and PD14, and PSA-NCAM expression and localization in neonates’ hippocampi were analyzed by Western blots and immunohistochemistry.

Results

Our data show a significant down regulation of hippocampal PSA-NCAM expression in the offspring of Kind⁺/Seiz⁺ (p = 0.001) and Kind^-/Seiz⁺ (p = 0.001) groups compared to the sham control group. The PSA-NCAM immunoreactivity was markedly decreased in all parts of the hippocampus, especially in the CA3 region, in Kind⁺/Seiz⁺ (p = 0.007) and Kind^-/Seiz⁺ (p = 0.007) group’s newborns on both PD1 and 14.

Conclusion

Our findings demonstrate that maternal seizures but not kindling influence the expression of PSA-NCAM in the offspring’s hippocampi, which may be considered as a factor for learning/memory and cognitive impairments reported in children born to epileptic mothers.     

Association of the CTLA4 Gene with Graves' Disease in the Chinese Han Population

To determine whether genetic heterogeneity exists in patients with Graves'' disease (GD), the cytotoxic T-lymphocyte associated 4 (CTLA-4) gene, which is implicated a susceptibility gene for GD by considerable genetic and immunological evidence, was used for association analysis in a Chinese Han cohort recruited from various geographic regions. Our association study for the SNPs in the CTLA4 gene in 2640 GD patients and 2204 control subjects confirmed that CTLA4 is the susceptibility gene for GD in the Chinese Han population. Moreover, the logistic regression analysis in the combined Chinese Han cohort revealed that SNP rs231779 (allele frequencies p = 2.81×10⁻⁹, OR = 1.35, and genotype distributions p = 2.75×10⁻⁹, OR = 1.42) is likely the susceptibility variant for GD. Interestingly, the logistic regression analysis revealed that SNP rs35219727 may be the susceptibility variant to GD in the Shandong population; however, SNP, rs231779 in the CTLA4 gene probably independently confers GD susceptibility in the Xuzhou and southern China populations. These data suggest that the susceptibility variants of the CTLA4 gene varied between the different geographic populations with GD.     

Demographic History,Adaptation, and NRAP Convergent Evolution at Amino Acid Residue 100 in the World Northernmost Cattle from Siberia

Native cattle breeds represent an important cultural heritage. They are a reservoir of genetic variation useful for properly responding to agriculture needs in the light of ongoing climate changes. Evolutionary processes that occur in response to extreme environmental conditions could also be better understood using adapted local populations. Herein, different evolutionary histories of the world northernmost native cattle breeds from Russia were investigated. They highlighted Kholmogory as a typical taurine cattle, whereas Yakut cattle separated from European taurines approximately 5,000 years ago and contain numerous ancestral and some novel genetic variants allowing their adaptation to harsh conditions of living above the Polar Circle. Scans for selection signatures pointed to several common gene pathways related to adaptation to harsh climates in both breeds. But genes affected by selection from these pathways were mostly different. A Yakut cattle breed-specific missense mutation in a highly conserved NRAP gene represents a unique example of a young amino acid residue convergent change shared with at least 16 species of hibernating/cold-adapted mammals from six distinct phylogenetic orders. This suggests a convergent evolution event along the mammalian phylogenetic tree and fast fixation in a single isolated cattle population exposed to a harsh climate.     

Promoter methylation analysis of WNT/β-catenin pathway regulators and its association with expression of DNMT1 enzyme in colorectal cancer

Background

Aberrant DNA methylation as the most important reason making epigenetic silencing of genes is a main mechanism of gene inactivation in patients with colorectal cancer. In this study, we decided to identify promoter methylation status of ten genes encoding WNT negative regulators, and measure the expression of DNMT1 enzyme in colorectal cancer samples.

Results

Aberrant methylation of APC gene was statistically significant associated with age over 50 (p = 0.017), DDK3 with male (p < 0.0001), SFRP4, WIF1, and WNT5a with increasing tumor stage (p = 0.004, p = 0.029, and p = 0.004), SFRP4 and WIF1 with tumor differentiation (p = 0.009 and p = 0.031) and SFRP2 and SFRP5 with histological type (p = 0.001 and p = 0.025). The increasing number of methylated genes correlated with the expression levels of the DNMT1 mRNA.

Conclusions

The rate of gene promoter methylation of WNT pathway regulators is high in colorectal cancer cells. Hyper-methylation is associated with increased expression of the DNMT1 enzyme.     

A genomic pathway approach to a complex disease: axon guidance and Parkinson disease

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10⁻³⁸), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10⁻⁴⁸), and PD age at onset (R² = 0.68, p = 1.68 × 10⁻⁵¹). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.     

Inferring the degree of incipient speciation in secondary contact zones of closely related lineages of Palearctic green toads (Bufo viridis subgroup)

Reproductive isolation between lineages is expected to accumulate with divergence time, but the time taken to speciate may strongly vary between different groups of organisms. In anuran amphibians, laboratory crosses can still produce viable hybrid offspring >20 My after separation, but the speed of speciation in closely related anuran lineages under natural conditions is poorly studied. Palearctic green toads (Bufo viridis subgroup) offer an excellent system to address this question, comprising several lineages that arose at different times and form secondary contact zones. Using mitochondrial and nuclear markers, we previously demonstrated that in Sicily, B. siculus and B. balearicus developed advanced reproductive isolation after Plio-Pleistocene divergence (2.6 My, 3.3–1.9), with limited historic mtDNA introgression, scarce nuclear admixture, but low, if any, current gene flow. Here, we study genetic interactions between younger lineages of early Pleistocene divergence (1.9 My, 2.5–1.3) in northeastern Italy (B. balearicus, B. viridis). We find significantly more, asymmetric nuclear and wider, differential mtDNA introgression. The population structure seems to be molded by geographic distance and barriers (rivers), much more than by intrinsic genomic incompatibilities. These differences of hybridization between zones may be partly explained by differences in the duration of previous isolation. Scattered research on other anurans suggests that wide hybrid zones with strong introgression may develop when secondary contacts occur <2 My after divergence, whereas narrower zones with restricted gene flow form when divergence exceeds 3 My. Our study strengthens support for this rule of thumb by comparing lineages with different divergence times within the same radiation.     

Evaluation of Neurotrophic Tyrosine Receptor Kinase 2 (NTRK2) as a positional candidate gene for variation in estimated Glomerular Filtration Rate (eGFR) in Mexican American participants of San Antonio Family Heart Study

Background

The estimated glomerular filtration rate (eGFR) is a well-known measure of kidney function and is commonly used for the diagnosis and management of patients with chronic kidney disease. The inter-individual variation in eGFR has significant genetic component. However, the identification of underlying genetic susceptibility variants has been challenging. In an attempt to identify and characterize susceptibility genetic variant(s) we previously identified the strongest evidence for linkage of eGFR occurring on chromosome 9q21 in the Mexican American participants of San Antonio Family Heart Study (SAFHS). The objective of the present study was to examine whether the common genetic variants in Neurotrophic Tyrosine Receptor Kinase 2 (NTRK2), a positional candidate gene on 9q21, contribute to variation in eGFR.

Results

Twelve tagging single nucleotide polymorphisms (SNPs) across the NTRK2 gene region were selected (r2 ≥ 0.80, minor allele frequency of ≥ 0.05) from the Hapmap database. SNPs were genotyped by TaqMan assay in the 848 Mexican American subjects participated in the SAFHS. Association analysis between the genotypes and eGFR (estimated by the Modification of Diet in Renal Disease equation) were performed by measured genotype approach as implemented in the program SOLAR. Of the 12 common genetic variants examined, the rs1036915 (located in 3′UTR) and rs1187274 (located in intron-14), present in perfect linkage disequilibrium, exhibited an association (P = 0.017) with eGFR after accounting for the effects of age, sex, diabetes, diabetes duration, systolic blood pressure and blood pressure medication. The carriers of minor allele of rs1036915 (G; 38%) had increased eGFR (104 ± 25 ml/min/1.73 m²) in comparison to the carriers of major allele A (98 ± 25 ml/min/1.73 m²).

Conclusion

Together, our results suggest for the first time that the genetic variants in NTRK2 may regulate eGFR.     

Exploring effects of DNA methylation and gene expression on pan-cancer drug response by mathematical models

Since genetic alteration only accounts for 20%–30% in the drug effect-related factors, the role of epigenetic regulation mechanisms in drug response is gradually being valued. However, how epigenetic changes and abnormal gene expression affect the chemotherapy response remains unclear. Therefore, we constructed a variety of mathematical models based on the integrated DNA methylation, gene expression, and anticancer drug response data of cancer cell lines from pan-cancer levels to identify genes whose DNA methylation is associated with drug response and then to assess the impact of epigenetic regulation of gene expression on the sensitivity of anticancer drugs. The innovation of the mathematical models lies in: Linear regression model is followed by logistic regression model, which greatly shortens the calculation time and ensures the reliability of results by considering the covariates. Second, reconstruction of prediction models based on multiple dataset partition methods not only evaluates the model stability but also optimizes the drug-gene pairs. For 368,520 drug-gene pairs with P < 0.05 in linear models, 999 candidate pairs with both AUC ≥ 0.8 and P < 0.05 were obtained by logistic regression models between drug response and DNA methylation. Then 931 drug-gene pairs with 45 drugs and 491 genes were optimized by model stability assessment. Integrating both DNA methylation and gene expression markedly increased predictive power for 732 drug-gene pairs where 598 drug-gene pairs including 44 drugs and 359 genes were prioritized. Several drug target genes were enriched in the modules of the drug-gene-weighted interaction network. Besides, for cancer driver genes such as EGFR, MET, and TET2, synergistic effects of DNA methylation and gene expression can predict certain anticancer drugs’ responses. In summary, we identified potential drug sensitivity-related markers from pan-cancer levels and concluded that synergistic regulation of DNA methylation and gene expression affect anticancer drug response.     

Divergence of a genomic island leads to the evolution of melanization in a halophyte root fungus

Understanding how organisms adapt to extreme living conditions is central to evolutionary biology. Dark septate endophytes (DSEs) constitute an important component of the root mycobiome and they are often able to alleviate host abiotic stresses. Here, we investigated the molecular mechanisms underlying the beneficial association between the DSE Laburnicola rhizohalophila and its host, the native halophyte Suaeda salsa, using population genomics. Based on genome-wide Fst (pairwise fixation index) and Vst analyses, which compared the variance in allele frequencies of single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs), respectively, we found a high level of genetic differentiation between two populations. CNV patterns revealed population-specific expansions and contractions. Interestingly, we identified a ~20 kbp genomic island of high divergence with a strong sign of positive selection. This region contains a melanin-biosynthetic polyketide synthase gene cluster linked to six additional genes likely involved in biosynthesis, membrane trafficking, regulation, and localization of melanin. Differences in growth yield and melanin biosynthesis between the two populations grown under 2% NaCl stress suggested that this genomic island contributes to the observed differences in melanin accumulation. Our findings provide a better understanding of the genetic and evolutionary mechanisms underlying the adaptation to saline conditions of the L. rhizohalophila–S. salsa symbiosis.Subject terms: Population dynamics, Fungal ecology, Population genetics     

An extensive candidate gene approach to speciation: diversity,divergence and linkage disequilibrium in candidate pigmentation genes across the European crow hybrid zone

Colouration patterns have an important role in adaptation and speciation. The European crow system, in which all-black carrion crows and grey-coated hooded crows meet in a narrow hybrid zone, is a prominent example. The marked phenotypic difference is maintained by assortative mating in the absence of neutral genetic divergence, suggesting the presence of few pigmentation genes of major effect. We made use of the rich phenotypic and genetic resources in mammals and identified a comprehensive panel of 95 candidate pigmentation genes for birds. Based on functional annotation, we chose a subset of the most promising 37 candidates, for which we developed a marker system that demonstrably works across the avian phylogeny. In total, we sequenced 107 amplicons (∼3 loci per gene, totalling 60 kb) in population samples of crows (n=23 for each taxon). Tajima''s D, Fu''s F_S, DHEW and HKA (Hudson–Kreitman–Aguade) statistics revealed several amplicons that deviated from neutrality; however, none of these showed significantly elevated differentiation between the two taxa. Hence, colour divergence in this system may be mediated by uncharacterized pigmentation genes or regulatory regions outside genes. Alternatively, the observed high population recombination rate (4N_er∼0.03), with overall linkage disequilibrium dropping rapidly within the order of few 100 bp, may compromise the power to detect causal loci with nearby markers. Our results add to the debate as to the utility of candidate gene approaches in relation to genomic features and the genetic architecture of the phenotypic trait in question.     

Identification of NF-κB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis

IntroductionSystemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility.MethodsSixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy).ResultsWe observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, P_adj = 7.22 × 10⁻⁵), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, P_adj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, P_adj = 2.49 × 10⁻⁴) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (P_adj = 4.45 × 10⁻⁴ and P_adj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (P_adj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10⁻⁴) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele.ConclusionsAn analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0572-y) contains supplementary material, which is available to authorized users.     

Population genetics of malaria resistance in humans

The high mortality and widespread impact of malaria have resulted in this disease being the strongest evolutionary selective force in recent human history, and genes that confer resistance to malaria provide some of the best-known case studies of strong positive selection in modern humans. I begin by reviewing JBS Haldane''s initial contribution to the potential of malaria genetic resistance in humans. Further, I discuss the population genetics aspects of many of the variants, including globin, G6PD deficiency, Duffy, ovalocytosis, ABO and human leukocyte antigen variants. Many of the variants conferring resistance to malaria are ‘loss-of-function'' mutants and appear to be recent polymorphisms from the last 5000–10 000 years or less. I discuss estimation of selection coefficients from case–control data and make predictions about the change for S, C and G6PD-deficiency variants. In addition, I consider the predicted joint changes when the two β-globin alleles S and C are both variable in the same population and when there is a variation for α-thalassemia and S, two unlinked, but epistatic variants. As more becomes known about genes conferring genetic resistance to malaria in humans, population genetics approaches can contribute both to investigating past selection and predicting the consequences in future generations for these variants.