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The cilia- and flagella-associated protein 43 (CFAP43) gene encodes a member of the cilia- and flagellum-associated protein family. Cilia on the cell surface influence intercellular signaling and are involved in biological processes such as osteogenesis and energy metabolism in animals. Previous studies have shown that insertion/deletion (InDel) variants in the CFAP43 gene affect litter size in Shaanbei white cashmere (SBWC) goats, and that litter size and body traits are correlated in this breed. Therefore, we hypothesized that there is a significant relationship between InDel variants within the CFAP43 gene and body traits in SBWC goats. Herein, we first investigated the association between three InDel variant loci (L-13, L-16, and L-19 loci) within CFAP43 and body traits in SBWC goats (n = 1827). Analyses revealed that the L-13, L-16, and L-19 loci were significantly associated with chest depth, four body traits, and three body traits, respectively. The results of this study are in good agreement with those previously reported and could provide useful molecular markers for the selection and breeding of goats for body traits.

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Whilst substantial research effort has been placed on understanding the interactions of plant proteins with their molecular partners, relatively few studies in plants - by contrast to work in other organisms - address how these interactions evolve. It is thought that ancestral proteins were more promiscuous than modern proteins and that specificity often evolved following gene duplication and subsequent functional refining. However, ancestral protein resurrection studies have found that some modern proteins have evolved de novo from ancestors lacking those functions. Intriguingly, the new interactions evolved as a consequence of just a few mutations and, as such, acquisition of new functions appears to be neither difficult nor rare, however, only a few of them are incorporated into biological processes before they are lost to subsequent mutations. Here, we detail the approach of ancestral sequence reconstruction (ASR), providing a primer to reconstruct the sequence of an ancestral gene. We will present case studies from a range of different eukaryotes before discussing the few instances where ancestral reconstructions have been used in plants. As ASR is used to dig into the remote evolutionary past, we will also present some alternative genetic approaches to investigate molecular evolution on shorter timescales. We argue that the study of plant secondary metabolism is particularly well suited for ancestral reconstruction studies. Indeed, its ancient evolutionary roots and highly diverse landscape provide an ideal context in which to address the focal issue around the emergence of evolutionary novelties and how this affects the chemical diversification of plant metabolism.

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Retroduplication variation (RDV), a type of retrocopy polymorphism, is considered to have essential biological significance, but its effect on gene function and species phenotype is still poorly understood. To this end, we analyzed the retrocopies and RDVs in 3,010 rice genomes. We calculated the RDV frequencies in the genome of each rice population; detected the mutated, ancestral and expressed retrogenes in rice genomes; and analyzed their RDV influence on rice phenotypic traits. Collectively, 73 RDVs were identified, and 14 RDVs in ancestral retrogenes can significantly affect rice phenotypes. Our research reveals that RDV plays an important role in rice migration, domestication and evolution. We think that RDV is a good molecular breeding marker candidate. To our knowledge, this is the first study on the relationship between retrogene function, expression, RDV and species phenotype.

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Genetic variants are major determinants of susceptibility to disease, response to therapy, and clinical outcomes. Advances in the short-read sequencing technologies, despite some shortcomings, have enabled identification of the vast majority of the genetic variants in each genome. The major challenge is in identifying the pathogenic variants in cardiovascular diseases. The yield of the genetic testing has been limited because of technological shortcomings and our incomplete understanding of the genetic basis of cardiovascular disorders. To advance the field, a shift to long-read sequencing platforms is necessary. In addition, to discern the pathogenic variants, genetic diseases should be considered as a continuum and the genetic variants as probabilistic factors with a gradient of effect sizes. Moreover, disease-specific physician-scientists with expertise in the clinical medicine and molecular genetics are best equipped to discern functional and clinical significance of the genetic variants. The changes would be expected to enhance clinical utilities of the genetic discoveries.

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BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases with simple steatosis on one end and hepatocellular carcinoma on the other. Although obesity is a known risk factor for NAFLD, individuals with normal body mass index (BMI) also have hepatic fatty infiltration, now termed "lean-NAFLD". It represents a distinct entity with a strong underlying genetic component. The present study aimed to sequence the complete exonic regions of individuals with lean-NAFLD to identify germline causative variants associated with disrupted hepatic fatty acid metabolism, thereby conferring susceptibility to NAFLD. METHODS: Whole blood was collected from patients with lean-NAFLD (n = 6; BMI < 23.0 kg/m2) and matched lean controls (n = 2; discovery set). Liver fat was assessed using acoustic radiation force impulse (ARFI) imaging. Patients with ultrasound-detected NAFLD (n = 191) and controls (n = 105) were part of validation set. DNA was isolated, and whole-exome sequencing (WES) was performed in the discovery cohort (Ion Proton™; Ion AmpliSeq™ Exome RDY Kit). Data were analyzed (Ion Reporter software; Life Technologies), and variants identified. Validation of variants was carried out (Taqman probes; Real time-PCR). Student's t test and Fisher's exact test were used to analyze the statistical significance. RESULTS: Although WES identified ∼74,000 variants in individual samples, using various pipelines. variants in genes namely phosphatidylethanolamine N-methyltransferase (PEMT) and oxysterol-binding protein-related protein10 (OSBPL10) that have roles in dietary choline intake and regulation of cholesterol homeostasis, respectively, were identified (discovery set). Furthermore, significant differences were noted in BMI (p = 0.006), waist/hip circumference (p > 0.001), waist/hip ratio (p > 0.001), aspartate aminotransferase (p > 0.001), alanine aminotransferase (p > 0.001), and triglycerides (p = 0.002) between patients and controls. Validation of variants (rs7946-PEMT and rs2290532-OSBPL10) revealed that variant in PEMT but not OSBPL10 gene was associated (p = 0.04) with threefold increased risk of NAFLD in lean individuals. CONCLUSION: Our results demonstrate the association of rs7946 with lean-NAFLD. WES may be an effective strategy to identify causative variants underlying lean-NAFLD.

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Background & Aims: Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study. Methods: We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients. Results: Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1-7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis. Conclusions: The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome-phenome archive (accession: EGAS00001002477).

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Lysine-specific demethylase 1B (KDM1B) which plays a crucial role in regulating methylation status at lysine 4 of histone 3 is important for male fertility. The aim of this study was to explore the KDM1B mRNA expression profiles and to identify novel genetic variants of the pig KDM1B gene, as well as to determine the association between these variants and testis measurement traits in male piglets. The KDM1B mRNA expression profiles indicated that this gene widely expressed in all tested organs. In addition, a novel 17-bp deletion (NC_010449.4:g.31142_31159delCATGGATAGTAGTTGCT) within KDM1B gene was found. Notably, this deletion sequence was inconsistent with the prediction by NCBI. Association analysis revealed that the 17-bp indel locus was significantly associated with the testis weight in 40-day-old Large White pigs (P < 0.05). Furthermore, through bioinformatics analysis, transcriptional factor heat shock factor-1 could combine the 17-bp sequence. These results not only extend the genetic variations of the pig KDM1B gene but also contribute to implementing marker-assisted selection in pig breeding.

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Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product-precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.

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