Concerted variation in melanogenesis genes underlies emergent patterning of plumage in capuchino seedeaters

Coloration traits are central to animal communication; they often govern mate choice, promote reproductive isolation and catalyse speciation. Specific genetic changes can cause variation in coloration, yet far less is known about how overall coloration patterns—which involve combinations of multiple colour patches across the body—can arise and are genomically controlled. We performed genome-wide association analyses to link genomic changes to variation in melanin (eumelanin and pheomelanin) concentration in feathers from different body parts in the capuchino seedeaters, an avian radiation with diverse colour patterns despite remarkably low genetic differentiation across species. Cross-species colour variation in each plumage patch is associated with unique combinations of variants at a few genomic regions, which include mostly non-coding (presumably regulatory) areas close to known pigmentation genes. Genotype–phenotype associations can vary depending on patch colour and are stronger for eumelanin pigmentation, suggesting eumelanin production is tightly regulated. Although some genes are involved in colour variation in multiple patches, in some cases, the SNPs associated with colour changes in different patches segregate spatially. These results suggest that coloration patterning in capuchinos is generated by the modular combination of variants that regulate multiple melanogenesis genes, a mechanism that may have promoted this rapid radiation.

Elevated FAM84B promotes cell proliferation via interacting with NPM1 in esophageal squamous cell carcinoma

Family with sequence similarity 84, member B (FAM84B) is a significant copy number amplification gene in the 8q24.21 locus identified by our previous WGS study in esophageal squamous cell carcinoma (ESCC). However, its clinical relevance and potential mechanisms have been elusive. Here, we performed the association analyses between FAM84BAmp and clinicopathological features using our dataset with 507 ESCC samples. The results indicated that, compared with the FAM84Bnon-Amp patients, the FAM84BAmp patients showed a more aggressive and a worse prognosis. Significant correlation was discovered between the expression level of FAM84B and FAM84BAmp in ESCC cohort. Furthermore, we found that the forced expression change of FAM84B can influence ESCC cell proliferation and cell cycle status, which is probably mediated by NPM1. A direct interaction between FAM84B and the C-terminal (189-294aa) of NPM1 was identified, which increased the NPM1 nuclear expression. Over-expression of NPM1 could inhibit the CDKN2A protein expression, which might affect the ESCC cell cycle. Our results indicate FAM84B CNA may be a potential diagnostic and therapeutic biomarker in ESCC, meanwhile, reveal a novel mechanism of FAM84B that it promotes tumorigenesis via interacting with NPM1 and suppressing CDKN2A.

DeepNull models non-linear covariate effects to improve phenotypic prediction and association power

Genome-wide association studies (GWASs) examine the association between genotype and phenotype while adjusting for a set of covariates. Although the covariates may have non-linear or interactive effects, due to the challenge of specifying the model, GWAS often neglect such terms. Here we introduce DeepNull, a method that identifies and adjusts for non-linear and interactive covariate effects using a deep neural network. In analyses of simulated and real data, we demonstrate that DeepNull maintains tight control of the type I error while increasing statistical power by up to 20% in the presence of non-linear and interactive effects. Moreover, in the absence of such effects, DeepNull incurs no loss of power. When applied to 10 phenotypes from the UK Biobank (n = 370K), DeepNull discovered more hits (+6%) and loci (+7%), on average, than conventional association analyses, many of which are biologically plausible or have previously been reported. Finally, DeepNull improves upon linear modeling for phenotypic prediction (+23% on average).

Genome-wide Discovery for Diabetes-Dependent Triglycerides-Associated Loci

Objective: Discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). Research Design and Methods: Genome-wide association study (GWAS) was performed in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels. Association analyses of TG levels were performed stratified by T2D status for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochrans Q-test implemented in METAL (p-value<5x10-8). Validation of significant variants was pursued in 25,137 participants of the Mass General Brigham Biobank (MGBB). Results: Among 21,176 T2D and 402,944 non-T2D samples, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2=98.4%; pheterogeneity=2.1x10-15), with log(TG) effect estimates of -0.066 (95%CI: -0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity=9.5x10-3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications. Conclusion: An intergenic variant near HLA-DQB1 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.

Construction of Genetic Linkage Maps From a Hybrid Family of Large Yellow Croaker (Larimichthys crocea)

Consensus and sex-specific genetic linkage maps for large yellow croaker (Larimichthys crocea) were constructed using samples from an F1 family produced by crossing a Daiqu female and a Mindong male. A total of 20,147 single nucleotide polymorphisms (SNPs) by restriction site associated DNA sequencing were assigned to 24 linkage groups (LGs). The total length of the consensus map was 1757.4 centimorgan (cM) with an average marker interval of 0.09 cM. The total length of female and male linkage map was 1533.1 cM and 1279.2 cM, respectively. The average female-to-male map length ratio was 1.2 ± 0.23. Collapsed markers in the genetic maps were re-ordered according to their relative positions in the ASM435267v1 genome assembly to produce integrated genetic linkage maps with 9885 SNPs distributed across the 24 LGs. The recombination pattern of most LGs showed sigmoidal patterns of recombination, with higher recombination in the middle and suppressed recombination at both ends, which corresponds with the presence of sub-telocentric and acrocentric chromosomes in the species. The average recombination rate in the integrated female and male maps was respectively 3.55 cM/Mb and 3.05 cM/Mb. In most LGs, higher recombination rates were found in the integrated female map, compared to the male map, except in LG12, LG16, LG21, LG22, and LG24. Recombination rate profiles within each LG differed between the male and the female, with distinct regions indicating potential recombination hotspots. Separate quantitative trait loci (QTL) and association analyses for growth related traits in 6 months fish were performed, however, no significant QTL was detected. The study indicates that there may be genetic differences between the two strains, which may have implications for the application of DNA-information in the further breeding schemes.

Exome sequencing of 628,388 individuals identifies common and rare variant associations with clonal hematopoiesis phenotypes

Clonal hematopoiesis (CH) refers to the expansion of certain blood cell lineages and has been associated with aging and adverse health outcomes. Here, we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal hematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 27 loci (24 novel) where germline genetic variation influences CH/CHIP predisposition, including missense variants in the DNA-repair gene PARP1 and the lymphocytic antigen coding gene LY75 that are associated with reduced incidence of CH/CHIP. Analysis of 5,194 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID outcomes, cardiovascular disease, hematologic traits, malignancy, smoking, obesity, infection, and all-cause mortality. Longitudinal analyses revealed that one of the CHIP subtypes, DNMT3A-CHIP, is associated with the subsequent development of myeloid but not lymphoid leukemias, and with solid cancers including prostate and lung. Additionally, contrary to previous findings from the initial 50,000 UKB exomes, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogenous phenotypes with shared and unique germline genetic causes and varied clinical implications.

Identification of Somatostatin Receptor Subtype 1 (SSTR1) Gene Polymorphism and Their Association with Growth Traits in Hulun Buir Sheep

This study was conducted to evaluate SSTR1 gene polymorphisms and their association with growth traits in Hulun Buir sheep. We followed 233 Hulun Buir sheep from birth to 16 months of age, born in the same pasture and on the same year under a consistent grazing conditions. The body weight (BW), body height (BH), body length (BL), chest circumference (ChC), chest depth (ChD), chest width (ChW), hip width (HW), and cannon circumference (CaC) were measured and recorded at birth, 4 months, 9 months, and 16 months of age. The polymorphisms of the SSTR1 gene in Hulun Buir sheep were excavated using exon sequencing, and association analyses of between SNPs and growth traits at each growth stage were conducted. The results showed that there were four SNPs in Exon 2 of the SSTR1 gene, SNP1, SNP2, and SNP3 were low mutation sites, and SNP4 was a moderate mutation site. Four SNPs were consistent with Hardy–Weinberg equilibrium, and all of them were synonymous mutations. The association analyses found that the genotypes of SNP2 were significantly associated with WW and BH at 4 months of age, BW, BL, ChC, and HW at 9 months of age (p < 0.05), and extremely significantly associated with ChD at 4 and 9 months of age (p < 0.01). There were significant associations between SNP3 and BH at 9 months of age, between SNP4 and ChD, ChW, and CaC at 9 months of age, and BW and ChC at 16 months of age (p < 0.05). There were no detectable associations with growth traits among the seven haplotypes between the SNP1, 3, and 4 of a strong linkage disequilibrium (p > 0.05). These results indicated that SNP2, SNP3, and SNP4 may be used as molecular markers for growth traits of Hulun Buir sheep.

Hepatic transcriptome analysis identifies genes, polymorphisms and pathways involved in the fatty acids metabolism in sheep

Fatty acids (FA) in ruminants, especially unsaturated FA (USFA) have important impact in meat quality, nutritional value, and flavour quality of meat, and on consumer’s health. Identification of the genetic factors controlling the FA composition and metabolism is pivotal to select sheep that produce higher USFA and lower saturated (SFA) for the benefit of sheep industry and consumers. Therefore, this study was aimed to investigate the transcriptome profiling in the liver tissues collected from sheep with divergent USFA content in longissimus muscle using RNA deep-sequencing. From sheep (n = 100) population, liver tissues with higher (n = 3) and lower (n = 3) USFA content were analysed using Illumina HiSeq 2500. The total number of reads produced for each liver sample were ranged from 21.28 to 28.51 million with a median of 23.90 million. Approximately, 198 genes were differentially regulated with significance level of p-adjusted value <0.05. Among them, 100 genes were up-regulated, and 98 were down-regulated (p<0.01, FC>1.5) in the higher USFA group. A large proportion of key genes involved in FA biosynthesis, adipogenesis, fat deposition, and lipid metabolism were identified, such as APOA5, SLC25A30, GFPT1, LEPR, TGFBR2, FABP7, GSTCD, and CYP17A. Pathway analysis revealed that glycosaminoglycan biosynthesis- keratan sulfate, adipokine signaling, galactose metabolism, endocrine and other factors-regulating calcium metabolism, mineral metabolism, and PPAR signaling pathway were playing important regulatory roles in FA metabolism. Importantly, polymorphism and association analyses showed that mutation in APOA5, CFHR5, TGFBR2 and LEPR genes could be potential markers for the FA composition in sheep. These polymorphisms and transcriptome networks controlling the FA variation could be used as genetic markers for FA composition-related traits improvement. However, functional validation is required to confirm the effect of these SNPs in other sheep population in order to incorporate them in the sheep breeding program.

Clinicopathological and Prognostic Significance of ABCC3 in Human Glioma

Glioma is the most common malignant primary brain tumor with an inferior survival period and unsatisfactory prognoses. Identification of novel biomarkers is important for the improvements of clinical outcomes of glioma patients. In recent years, more and more biomarkers were identified in many types of tumors. However, the sensitive markers for diagnoses and prognoses of patients with glioma remained unknown. In the present research, our team intended to explore the expression and clinical significance of ABCC3 in glioma patients. Sequential data filtration (survival analyses, independent prognosis analyses, ROC curve analyses, and clinical association analyses) was completed, which gave rise to the determination of the relationship between glioma and the ABCC3 gene. Clinical assays on the foundation of CGGA and TCGA datasets unveiled that ABCC3 expression was distinctly upregulated in glioma and predicted a shorter overall survival. In the multivariable Cox analysis, our team discovered that the expression of ABCC3 was an independent prognosis marker for both 5-year OS (HR = 1.118, 95% CI: 1.052–1.188; P < 0.001 ). Moreover, our team also studied the association between ABCC3 expression and clinical features of glioma patients, finding that differential expression of ABCC3 was remarkably related to age, 1p19q codeletion, PRS type, chemo status, grade, IDH mutation state, and histology. Overall, our findings suggested ABCC3 might be a novel prognosis marker in glioma.

HLA-B27 and not variation in MICA is responsible for genotype by sex interaction in risk of Ankylosing Spondylitis

Ankylosing Spondylitis (AS) is a highly heritable inflammatory arthritis which occurs more frequently in men than women. In their recent publication examining sex differences in the genetic aetiology of common complex traits and diseases, Bernabeu et al. (2021) observe differences in heritability of AS between sexes, and a genome-wide significant genotype by sex interaction in risk of AS at the major histocompatability (MHC) locus. The authors then present evidence suggesting that this genotype by sex interaction arises primarily as a result of differential expression of the gene MICA across the sexes in skeletal muscle tissue. Through a series of conditional association analyses in the UK Biobank, reanalysis of the GTEx gene expression resource and RNASeq experiments on peripheral blood cells from AS cases and controls, we show that the genotype by sex interaction the authors' report is unlikely to be a result of variation in MICA, but probably reflects a known interaction between the HLA-B gene, sex and risk of AS. We demonstrate that the diagnostic accuracy of AS in the UK Biobank is low, particularly amongst women, likely explaining some of the observed differences in heritability across the sexes and the difficulty in precisely locating association signals in the cohort.