ResearchPad - genetic-loci https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Polyploidy breaks speciation barriers in Australian burrowing frogs <i>Neobatrachus</i>]]> https://www.researchpad.co/article/elastic_article_16332 Polyploidy or whole genome duplication is rare in animals and usually polyploid animals reproduce asexually. The Australian burrowing frogs of the genus Neobatrachus form an interesting exception amongst vertebrates with multiple independently originated autotetraploid sexual species. We generated population genomic data from 87 animals representing all six diploid and three tetraploid species of Neobatrachus. We show that, while diploid Neobatrachus species seem to be isolated from each other, their sister tetraploid species experience substantial levels of gene flow, and have wider distributions. Furthermore, we observe asymmetric gene flow from diploids to tetraploids. Based on our genomic and climate analyses we suggest that such inter-specific hybridization mediated by whole genome duplication rescues species diversity and allows tetraploids to more easily avoid impacts of climate-induced habitat loss.

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<![CDATA[Genome-wide association study of partial resistance to sclerotinia stem rot of cultivated soybean based on the detached leaf method]]> https://www.researchpad.co/article/elastic_article_15721 Sclerotinia stem rot (SSR) is a devastating fungal disease that causes severe yield losses of soybean worldwide. In the present study, a representative population of 185 soybean accessions was selected and utilized to identify the quantitative trait nucleotide (QTN) of partial resistance to soybean SSR via a genome-wide association study (GWAS). A total of 22,048 single-nucleotide polymorphisms (SNPs) with minor allele frequencies (MAF) > 5% and missing data < 3% were used to assess linkage disequilibrium (LD) levels. Association signals associated with SSR partial resistance were identified by two models, including compressed mixed linear model (CMLM) and multi-locus random-SNP-effect mixed linear model (mrMLM). Finally, seven QTNs with major effects (a known locus and six novel loci) via CMLM and nine novel QTNs with minor effects via mrMLM were detected in relation to partial resistance to SSR, respectively. One of all the novel loci (Gm05:14834789 on Chr.05), which was co-located by these two methods, might be a stable one that showed high significance in SSR partial resistance. Additionally, a total of 71 major and 85 minor candidate genes located in the 200-kb genomic region of each peak SNP detected by CMLM and mrMLM were found, respectively. By using a gene-based association, a total of six SNPs from three major effects genes and eight SNPs from four minor effects genes were identified. Of them, Glyma.18G012200 has been characterized as a significant element in controlling fungal disease in plants.

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<![CDATA[A genome-wide association study of deafness in three canine breeds]]> https://www.researchpad.co/article/elastic_article_14705 Congenital deafness in the domestic dog is usually related to the presence of white pigmentation, which is controlled primarily by the piebald locus on chromosome 20 and also by merle on chromosome 10. Pigment-associated deafness is also seen in other species, including cats, mice, sheep, alpacas, horses, cows, pigs, and humans, but the genetic factors determining why some piebald or merle dogs develop deafness while others do not have yet to be determined. Here we perform a genome-wide association study (GWAS) to identify regions of the canine genome significantly associated with deafness in three dog breeds carrying piebald: Dalmatian, Australian cattle dog, and English setter. We include bilaterally deaf, unilaterally deaf, and matched control dogs from the same litter, phenotyped using the brainstem auditory evoked response (BAER) hearing test. Principal component analysis showed that we have different distributions of cases and controls in genetically distinct Dalmatian populations, therefore GWAS was performed separately for North American and UK samples. We identified one genome-wide significant association and 14 suggestive (chromosome-wide) associations using the GWAS design of bilaterally deaf vs. control Australian cattle dogs. However, these associations were not located on the same chromosome as the piebald locus, indicating the complexity of the genetics underlying this disease in the domestic dog. Because of this apparent complex genetic architecture, larger sample sizes may be needed to detect the genetic loci modulating risk in piebald dogs.

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<![CDATA[Fine-scale population genetic structure of dengue mosquito vector, <i>Aedes aegypti</i>, in Metropolitan Manila, Philippines]]> https://www.researchpad.co/article/elastic_article_14656 Aedes aegypti is an efficient vector of dengue due to its highly adaptive nature to the urban environment. Although it is observed to have a short dispersal (active) capability, it has been shown to be capable of traveling long distances (passive) via human-mediated transportation. This duality may expand the distribution of the mosquito vector in urbanized areas. In this study, we examined the population genetic structure of Ae. aegypti in a highly urbanized and dengue-endemic region of the Philippines, Metropolitan Manila. Our findings indicated the dual dispersal nature of Ae. aegypti. The use of microsatellites as genetic markers also allowed us to describe the potential long-distance dispersal patterns, possibly through human-aided land transportation via the existing road networks of Metropolitan Manila.

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<![CDATA[Simultaneous SNP selection and adjustment for population structure in high dimensional prediction models]]> https://www.researchpad.co/article/elastic_article_14653 This work addresses a recurring challenge in the analysis and interpretation of genetic association studies: which genetic variants can best predict and are independently associated with a given phenotype in the presence of population structure? Not controlling confounding due to geographic population structure, family and/or cryptic relatedness can lead to spurious associations. Much of the existing research has therefore focused on modeling the association between a phenotype and a single genetic variant in a linear mixed model with a random effect. However, this univariate approach may miss true associations due to the stringent significance thresholds required to reduce the number of false positives and also ignores the correlations between markers. We propose an alternative method for fitting high-dimensional multivariable models, which selects SNPs that are independently associated with the phenotype while also accounting for population structure. We provide an efficient implementation of our algorithm and show through simulation studies and real data examples that our method outperforms existing methods in terms of prediction accuracy and controlling the false discovery rate.

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<![CDATA[Association between the rs1544410 polymorphism in the vitamin D receptor (VDR) gene and insulin secretion after gestational diabetes mellitus]]> https://www.researchpad.co/article/elastic_article_14643 Genetic variants involved in vitamin D metabolism have been associated with diabetes and related syndromes/diseases. We wanted to investigate possible associations of polymorphisms in genes involved in vitamin D metabolism with indices of insulin resistance and insulin secretion, and also with development of diabetes after gestational diabetes mellitus (GDM).Materials and methodsWe have studied 376 women with previous GDM. Eight single nucleotide polymorphisms (SNPs) in the genes for vitamin D receptor (VDR) [rs731236, rs7975232, rs10735810, and rs1544410], vitamin D binding protein (DBP) [rs7041 and rs4588], and cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [rs10877012 and rs4646536] were genotyped by TaqMan Allelic Discrimination Assay using the Quantstudio 7 Flex system. A 75-g oral glucose tolerance test (OGTT) was performed 1–2 years postpartum. The homeostasis model assessment of insulin resistance (HOMA-IR) and the disposition index [(insulinogenic index: I30/G30)/HOMA-IR] were used to calculate insulin resistance and insulin secretion, respectively. Serum samples for determination of 25(OH)D3 were collected at the time of the OGTT. Manifestation of diabetes was followed up to five years postpartum.ResultsAfter adjustment for BMI, age, and ethnicity, the A-allele of the VDR rs1544410 polymorphism was found to be associated with increased disposition index (difference per allele = 3.56, 95% CI: 0.4567–6.674; p = 0.03). The A-allele of the DBP rs7041 polymorphism was found to be associated with 25(OH)D3 levels (difference [in nmol/L] per allele = −5.478, 95% CI: -8.315 to −2.641; p = 0.0002), as was the T-allele of the DBP rs4588 polymorphism (OR = −6.319, 95% CI: −9.466 to −3.171; p = 0.0001). None of the SNPs were significantly associated with HOMA-IR or postpartum diabetes.ConclusionsThis study provides evidence that the rs1544410 polymorphism of the VDR gene may be associated with increased insulin secretion in women after pregnancy complicated by GDM. Further studies in other populations are needed to confirm the results. ]]> <![CDATA[An improved 7K SNP array, the C7AIR, provides a wealth of validated SNP markers for rice breeding and genetics studies]]> https://www.researchpad.co/article/elastic_article_14581 Single nucleotide polymorphisms (SNPs) are highly abundant, amendable to high-throughput genotyping, and useful for a number of breeding and genetics applications in crops. SNP frequencies vary depending on the species and populations under study, and therefore target SNPs need to be carefully selected to be informative for each application. While multiple SNP genotyping systems are available for rice (Oryza sativa L. and its relatives), they vary in their informativeness, cost, marker density, speed, flexibility, and data quality. In this study, we report the development and performance of the Cornell-IR LD Rice Array (C7AIR), a second-generation SNP array containing 7,098 markers that improves upon the previously released C6AIR. The C7AIR is designed to detect genome-wide polymorphisms within and between subpopulations of O. sativa, as well as O. glaberrima, O. rufipogon and O. nivara. The C7AIR combines top-performing SNPs from several previous rice arrays, including 4,007 SNPs from the C6AIR, 2,056 SNPs from the High Density Rice Array (HDRA), 910 SNPs from the 384-SNP GoldenGate sets, 189 SNPs from the 44K array selected to add information content for elite U.S. tropical japonica rice varieties, and 8 trait-specific SNPs. To demonstrate its utility, we carried out a genome-wide association analysis for plant height, employing the C7AIR across a diversity panel of 189 rice accessions and identified 20 QTLs contributing to plant height. The C7AIR SNP chip has so far been used for genotyping >10,000 rice samples. It successfully differentiates the five subpopulations of Oryza sativa, identifies introgressions from wild and exotic relatives, and is useful for quantitative trait loci (QTL) and association mapping in diverse materials. Moreover, data from the C7AIR provides valuable information that can be used to select informative and reliable SNP markers for conversion to lower-cost genotyping platforms for genomic selection and other downstream applications in breeding.

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<![CDATA[Genetic variation and phylogeographic structure of <i>Spodoptera exigua</i> in western China based on mitochondrial DNA and microsatellite markers]]> https://www.researchpad.co/article/elastic_article_14552 The beet armyworm, Spodoptera exigua, is a significant agricultural pest of numerous crops and has caused serious economic losses in China. To effectively control this pest, we analyzed its genetic variation, population genetic structure and demographic history. We used mitochondrial DNA (mtDNA) fragments of the cytochrome oxidase subunit I (COI) and eight nuclear microsatellite loci to investigate genetic diversity and population genetic structure of S. exigua populations at 14 sampling sites in western China. Both mtDNA and microsatellite data indicated low levels of genetic diversity among all populations. A moderate genetic differentiation among some S. exigua populations was detected. Neighbor-joining dendrograms, STRUCTURE, and principal coordinate analysis (PCoA) revealed two genetically distinct groups: the KEL group and the remaining population group. Isolation by distance (IBD) results showed a weak significant correlation between geographic distance and genetic differentiation. Haplotype networks, neutrality testing, and mismatch distribution analysis indicated that the beet armyworm experienced a recent rapid expansion without a recent genetic bottleneck in western China. Thus, the results of this population genetic study can help with the development of strategies for managing this highly migratory pest.

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<![CDATA[SNP markers for low molecular glutenin subunits (LMW-GSs) at the <i>Glu-A3</i> and <i>Glu-B3</i> loci in bread wheat]]> https://www.researchpad.co/article/elastic_article_13817 The content and composition of seed storage proteins is largely responsible for wheat end-use quality. They mainly consist of polymeric glutenins and monomeric gliadins. According to their electrophoretic mobility, gliadins and glutenins are subdivided into several fractions. Glutenins are classified as high molecular weight or low molecular weight glutenin subunits (HMW-GSs and LMW-GSs, respectively). LMW-GSs are encoded by multigene families located at the orthologous Glu-3 loci. We designed a set of 16 single-nucleotide polymorphism (SNP) markers that are able to detect SDS-PAGE alleles at the Glu-A3 and Glu-B3 loci. The SNP markers captured the diversity of alleles in 88 international reference lines and 27 Mexican cultivars, when compared to SDS-PAGE and STS markers, however, showed a slightly larger percent of multiple alleles, mainly for Glu-B3. SNP markers were then used to determine the Glu-1 and Glu-3 allele composition in 54 CIMMYT historical lines and demonstrated to be useful tool for breeding programs to improve wheat end product properties.

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<![CDATA[Adaptive genetic diversity and evidence of population genetic structure in the endangered Sierra Madre Sparrow (<i>Xenospiza baileyi</i>)]]> https://www.researchpad.co/article/elastic_article_11235 The magnitude and distribution of genetic diversity through space and time can provide useful information relating to evolutionary potential and conservation status in threatened species. In assessing genetic diversity in species that are of conservation concern, several studies have focused on the use of Toll-like receptors (TLRs). TLRs are innate immune genes related to pathogen resistance, and polymorphisms may reflect not only levels of functional diversity, but may also be used to assess genetic diversity within and among populations. Here, we combined four potentially adaptive markers (TLRs) with one mitochondrial (COI) marker to evaluate genetic variation in the endangered Sierra Madre Sparrow (Xenospiza baileyi). This species offers an ideal model to investigate population and evolutionary genetic processes that may be occurring in a habitat restricted endangered species with disjunct populations (Mexico City and Durango), the census sizes of which differ by an order of magnitude. TLRs diversity in the Sierra Madre Sparrow was relatively high, which was not expected given its two small, geographically isolated populations. Genetic diversity was different (but not significantly so) between the two populations, with less diversity seen in the smaller Durango population. Population genetic structure between populations was due to isolation and different selective forces acting on different TLRs; population structure was also evident in COI. Reduction of genetic diversity in COI was observed over 20 years in the Durango population, a result likely caused by habitat loss, a factor which may be the main cause of diversity decline generally. Our results provide information related to the ways in which adaptive variation can be altered by demographic changes due to human-mediated habitat alterations. Furthermore, our findings may help to guide conservation schemes for both populations and their restricted habitat.

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<![CDATA[Paleogenetic study on the 17th century Korean mummy with atherosclerotic cardiovascular disease]]> https://www.researchpad.co/article/5aafccf3463d7e7f05234537

While atherosclerotic cardiovascular disease (ASCVD) is known to be common among modern people exposed to various risk factors, recent paleopathological studies have shown that it affected ancient populations much more frequently than expected. In 2010, we investigated a 17th century Korean female mummy with presumptive ASCVD signs. Although the resulting report was a rare and invaluable conjecture on the disease status of an ancient East Asian population, the diagnosis had been based only on anatomical and radiological techniques, and so could not confirm the existence of ASCVD in the mummy. In the present study, we thus performed a paleogenetic analysis to supplement the previous conventional diagnosis of ASCVD. In aDNA extracted from the same Korean mummy, we identified the risk alleles of seven different SNPs (rs5351, rs10757274, rs2383206, rs2383207, rs10757278, rs4380028 and rs1333049) that had already been revealed to be the major risk loci of ASCVD in East Asian populations. The reliability of this study could be enhanced by cross-validation using two different analyses: Sanger and SNaPshot techniques. We were able to establish that the 17th century Korean female had a strong genetic predisposition to increased risk of ASCVD. The current paleogenetic diagnosis, the first of its kind outside Europe, re-confirms its utility as an adjunct modality for confirmatory diagnosis of ancient ASCVD.

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<![CDATA[Evidence for both sequential mutations and recombination in the evolution of kdr alleles in Aedes aegypti]]> https://www.researchpad.co/article/N8479e8f6-b6ad-4aa7-91b1-bf6bde90184a

Background

Aedes aegypti is a globally distributed vector of human diseases including dengue, yellow fever, chikungunya, and Zika. Pyrethroid insecticides are the primary means of controlling adult A. aegypti populations to suppress arbovirus outbreaks, but resistance to pyrethroid insecticides has become a global problem. Mutations in the voltage-sensitive sodium channel (Vssc) gene are a major mechanism of pyrethroid resistance in A. aegypti. Vssc resistance alleles in A. aegypti commonly have more than one mutation. However, our understanding of the evolutionary dynamics of how alleles with multiple mutations arose is poorly understood.

Methodology/Principal findings

We examined the geographic distribution and association between the common Vssc mutations (V410L, S989P, V1016G/I and F1534C) in A. aegypti by analyzing the relevant Vssc fragments in 25 collections, mainly from Asia and the Americas. Our results showed all 11 Asian populations had two types of resistance alleles: 1534C and 989P+1016G. The 1534C allele was more common with frequencies ranging from 0.31 to 0.88, while the 989P+1016G frequency ranged from 0.13 to 0.50. Four distinct alleles (410L, 1534C, 410L+1534C and 410L+1016I+1534C) were detected in populations from the Americas. The most common was 410L+1016I+1534C with frequencies ranging from 0.50 to 1.00, followed by 1534C with frequencies ranging from 0.13 to 0.50. Our phylogenetic analysis of Vssc supported multiple independent origins of the F1534C mutation. Our results indicated the 410L+1534C allele may have arisen by addition of the V410L mutation to the 1534C allele, or by a crossover event. The 410L+1016I+1534C allele was the result of one or two mutational steps from a 1534C background.

Conclusions/Significance

Our data corroborated previous geographic distributions of resistance mutations and provided evidence for both recombination and sequential accumulation of mutations contributing to the molecular evolution of resistance alleles in A. aegypti.

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<![CDATA[Parallelism in eco-morphology and gene expression despite variable evolutionary and genomic backgrounds in a Holarctic fish]]> https://www.researchpad.co/article/N4fc7d71e-6de4-4251-8df9-22327ccf5952

Understanding the extent to which ecological divergence is repeatable is essential for predicting responses of biodiversity to environmental change. Here we test the predictability of evolution, from genotype to phenotype, by studying parallel evolution in a salmonid fish, Arctic charr (Salvelinus alpinus), across eleven replicate sympatric ecotype pairs (benthivorous-planktivorous and planktivorous-piscivorous) and two evolutionary lineages. We found considerable variability in eco-morphological divergence, with several traits related to foraging (eye diameter, pectoral fin length) being highly parallel even across lineages. This suggests repeated and predictable adaptation to environment. Consistent with ancestral genetic variation, hundreds of loci were associated with ecotype divergence within lineages of which eight were shared across lineages. This shared genetic variation was maintained despite variation in evolutionary histories, ranging from postglacial divergence in sympatry (ca. 10-15kya) to pre-glacial divergence (ca. 20-40kya) with postglacial secondary contact. Transcriptome-wide gene expression (44,102 genes) was highly parallel across replicates, involved biological processes characteristic of ecotype morphology and physiology, and revealed parallelism at the level of regulatory networks. This expression divergence was not only plastic but in part genetically controlled by parallel cis-eQTL. Lastly, we found that the magnitude of phenotypic divergence was largely correlated with the genetic differentiation and gene expression divergence. In contrast, the direction of phenotypic change was mostly determined by the interplay of adaptive genetic variation, gene expression, and ecosystem size. Ecosystem size further explained variation in putatively adaptive, ecotype-associated genomic patterns within and across lineages, highlighting the role of environmental variation and stochasticity in parallel evolution. Together, our findings demonstrate the parallel evolution of eco-morphology and gene expression within and across evolutionary lineages, which is controlled by the interplay of environmental stochasticity and evolutionary contingencies, largely overcoming variable evolutionary histories and genomic backgrounds.

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<![CDATA[Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil]]> https://www.researchpad.co/article/N0a09703b-e69a-40d3-8ae4-dfe23e56b45d

Introduction

The nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil.

Methods

The entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa® (Viewer of Variants) software.

Results

Four NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high frequencies in both our study populations in comparison with other populations catalogued in the 1000 Genomes database. We also identified the NUDT15*4 haplotype in our study populations, at frequencies similar to those reported in other populations from around the world.

Conclusion

Our findings indicate that Amerindian and admixed populations from northern Brazil have high frequencies of the NUDT15 haplotypes that alter the metabolism profile of thiopurines.

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<![CDATA[A framework for gene mapping in wheat demonstrated using the Yr7 yellow rust resistance gene]]> https://www.researchpad.co/article/N8aa5bdf2-6390-43c2-aef2-b7a76659179a

We used three approaches to map the yellow rust resistance gene Yr7 and identify associated SNPs in wheat. First, we used a traditional QTL mapping approach using a double haploid (DH) population and mapped Yr7 to a low-recombination region of chromosome 2B. To fine map the QTL, we then used an association mapping panel. Both populations were SNP array genotyped allowing alignment of QTL and genome-wide association scans based on common segregating SNPs. Analysis of the association panel spanning the QTL interval, narrowed the interval down to a single haplotype block. Finally, we used mapping-by-sequencing of resistant and susceptible DH bulks to identify a candidate gene in the interval showing high homology to a previously suggested Yr7 candidate and to populate the Yr7 interval with a higher density of polymorphisms. We highlight the power of combining mapping-by-sequencing, delivering a complete list of gene-based segregating polymorphisms in the interval with the high recombination, low LD precision of the association mapping panel. Our mapping-by-sequencing methodology is applicable to any trait and our results validate the approach in wheat, where with a near complete reference genome sequence, we are able to define a small interval containing the causative gene.

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<![CDATA[Generation of targeted homozygosity in the genome of human induced pluripotent stem cells]]> https://www.researchpad.co/article/Nc0b5af8d-f419-410c-9036-89fcaed1eba6

When loss of heterozygosity (LOH) is correlated with loss or gain of a disease phenotype, it is often necessary to identify which gene or genes are involved. Here, we developed a region-specific LOH-inducing system based on mitotic crossover in human induced pluripotent stem cells (hiPSCs). We first tested our system on chromosome 19. To detect homozygous clones generated by LOH, a positive selection cassette was inserted at the AASV1 locus of chromosome 19. LOHs were generated by the combination of allele-specific double-stranded DNA breaks introduced by CRISPR/Cas9 and suppression of Bloom syndrome (BLM) gene expression by the Tet-Off system. The BLM protein inhibitor ML216 exhibited a similar crossover efficiency and distribution of crossover sites. We next applied this system to the short arm of chromosome 6, where human leukocyte antigen (HLA) loci are located. Genotyping and flow cytometric analysis demonstrated that LOHs associated with chromosomal crossover occurred at the expected positions. Although careful examination of HLA-homozygous hiPSCs generated from parental cells is needed for cancer predisposition and effectiveness of differentiation, they may help to mitigate the current shortcoming of hiPSC-based transplantation related to the immunological differences between the donor and host.

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<![CDATA[Autosomal recessive congenital cataracts linked to HSF4 in a consanguineous Pakistani family]]> https://www.researchpad.co/article/Na302ecef-6336-4a97-9663-2461453833de

Purpose

To investigate the genetic basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous Pakistani family.

Methods

All participating members of family, PKCC074 underwent an ophthalmic examination. Slit-lamp photographs were ascertained for affected individuals that have not been operated for the removal of the cataractous lens. A small aliquot of the blood sample was collected from all participating individuals and genomic DNAs were extracted. A genome-wide scan was performed with polymorphic short tandem repeat (STR) markers and the logarithm of odds (LOD) scores were calculated. All coding exons and exon-intron boundaries of HSF4 were sequenced and expression of Hsf4 in mouse ocular lens was investigated. The C-terminal FLAG-tagged wild-type and mutant HSF4b constructs were prepared to examine the nuclear localization pattern of the mutant protein.

Results

The ophthalmological examinations suggested that nuclear cataracts are present in affected individuals. Genome-wide linkage analyses localized the critical interval to a 10.95 cM (14.17 Mb) interval on chromosome 16q with a maximum two-point LOD score of 4.51 at θ = 0. Sanger sequencing identified a novel missense mutation: c.433G>C (p.Ala145Pro) that segregated with the disease phenotype in the family and was not present in ethnically matched controls. Real-time PCR analysis identified the expression of HSF4 in mouse lens as early as embryonic day 15 with a steady level of expression thereafter. The immunofluorescence tracking confirmed that both wild-type and mutant HSF4 (p.Ala145Pro) proteins localized to the nucleus.

Conclusion

Here, we report a novel missense mutation in HSF4 associated with arCC in a familial case of Pakistani descent.

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<![CDATA[A novel nonsense variant in SUPT20H gene associated with Rheumatoid Arthritis identified by Whole Exome Sequencing of multiplex families]]> https://www.researchpad.co/article/5c8acceed5eed0c48499036b

The triggering and development of Rheumatoid Arthritis (RA) is conditioned by environmental and genetic factors. Despite the identification of more than one hundred genetic variants associated with the disease, not all the cases can be explained. Here, we performed Whole Exome Sequencing in 9 multiplex families (N = 30) to identify rare variants susceptible to play a role in the disease pathogenesis. We pre-selected 77 genes which carried rare variants with a complete segregation with RA in the studied families. Follow-up linkage and association analyses with pVAAST highlighted significant RA association of 43 genes (p-value < 0.05 after 106 permutations) and pinpointed their most likely causal variant. We re-sequenced the 10 most significant likely causal variants (p-value ≤ 3.78*10−3 after 106 permutations) in the extended pedigrees and 9 additional multiplex families (N = 110). Only one SNV in SUPT20H: c.73A>T (p.Lys25*), presented a complete segregation with RA in an extended pedigree with early-onset cases. In summary, we identified in this study a new variant associated with RA in SUPT20H gene. This gene belongs to several biological pathways like macro-autophagy and monocyte/macrophage differentiation, which contribute to RA pathogenesis. In addition, these results showed that analyzing rare variants using a family-based approach is a strategy that allows to identify RA risk loci, even with a small dataset.

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<![CDATA[FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele]]> https://www.researchpad.co/article/5c89776ad5eed0c4847d2c3f

FBXO7 encodes an F box containing protein that interacts with multiple partners to facilitate numerous cellular processes and has a canonical role as part of an SCF E3 ubiquitin ligase complex. Mutation of FBXO7 is responsible for an early onset Parkinsonian pyramidal syndrome and genome-wide association studies have linked variants in FBXO7 to erythroid traits. A putative orthologue in Drosophila, nutcracker, has been shown to regulate the proteasome, and deficiency of nutcracker results in male infertility. Therefore, we reasoned that modulating Fbxo7 levels in a murine model could provide insights into the role of this protein in mammals. We used a targeted gene trap model which retained 4–16% residual gene expression and assessed the sensitivity of phenotypic traits to gene dosage. Fbxo7 hypomorphs showed regenerative anaemia associated with a shorter erythrocyte half-life, and male mice were infertile. Alterations to T cell phenotypes were also observed, which intriguingly were both T cell intrinsic and extrinsic. Hypomorphic mice were also sensitive to infection with Salmonella, succumbing to a normally sublethal challenge. Despite these phenotypes, Fbxo7 hypomorphs were produced at a normal Mendelian ratio with a normal lifespan and no evidence of neurological symptoms. These data suggest that erythrocyte survival, T cell development and spermatogenesis are particularly sensitive to Fbxo7 gene dosage.

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<![CDATA[Comparison of infinitesimal and finite locus models for long-term breeding simulations with direct and maternal effects at the example of honeybees]]> https://www.researchpad.co/article/5c897737d5eed0c4847d272e

Stochastic simulation studies of animal breeding have mostly relied on either the infinitesimal genetic model or finite polygenic models. In this study, we investigated the long-term effects of the chosen model on honeybee breeding schemes. We implemented the infinitesimal model, as well as finite locus models, with 200 and 400 gene loci and simulated populations of 300 and 1000 colonies per year over the course of 100 years. The selection was of a directly and maternally influenced trait with maternal heritability of hm2=0.42, direct heritability of hd2=0.27, and a negative correlation between the effects of rmd = − 0.18. Another set of simulations was run with parameters hm2=0.53, hd2=0.34, and rmd = − 0.53. All models showed similar behavior for the first 20 years. Throughout the study, we observed a higher genetic gain in the direct than in the maternal effects and a smaller gain with a stronger negative covariance. In the long-term, however, only the infinitesimal model predicted sustainable linear genetic progress, while the finite locus models showed sublinear behavior and, after 100 years, only reached between 58% and 62% of the mean breeding values in the infinitesimal model. While the infinitesimal model suggested a reduction of genetic variance by 33% to 49% after 100 years, the finite locus models saw a more drastic loss of 76% to 92%. When designing sustainable breeding strategies, one should, therefore, not blindly trust the infinitesimal model as the predictions may be overly optimistic. Instead, the more conservative choice of the finite locus model should be favored.

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