Linkage Analysis
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Author(s):  
Xiao‐Juan Guo ◽  
Xing‐Biao Qiu ◽  
Jun Wang ◽  
Yu‐Han Guo ◽  
Chen‐Xi Yang ◽  
...  

Background Atrial fibrillation (AF) is the most common form of clinical cardiac dysrhythmia responsible for thromboembolic cerebral stroke, congestive heart failure, and death. Aggregating evidence highlights the strong genetic basis of AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of patients, the genetic determinants underpinning AF remain elusive. Methods and Results By genome‐wide screening with polymorphic microsatellite markers and linkage analysis in a 4‐generation Chinese family affected with autosomal‐dominant AF, a novel locus for AF was mapped to chromosome 1q24.2–q25.1, a 3.20‐cM (≈4.19 Mbp) interval between markers D1S2851 and D1S218, with the greatest 2‐point logarithm of odds score of 4.8165 for the marker D1S452 at recombination fraction=0.00. Whole‐exome sequencing and bioinformatics analyses showed that within the mapping region, only the mutation in the paired related homeobox 1 ( PRRX1 ) gene, NM_022716.4:c.319C>T;(p.Gln107*), cosegregated with AF in the family. In addition, sequencing analyses of PRRX1 in another cohort of 225 unrelated patients with AF revealed a new mutation, NM_022716.4:c.437G>T; (p.Arg146Ile), in a patient. The 2 mutations were absent in 908 control subjects. Biological analyses in HeLa cells demonstrated that the 2 mutants had significantly diminished transactivation on the target genes ISL1 and SHOX2 and markedly decreased ability to bind the promoters of ISL1 and SHOX2 (2 genes causally linked to AF), although with normal intracellular distribution. Conclusions This study first indicates that PRRX1 loss‐of‐function mutations predispose to AF, which provides novel insight into the molecular pathogenesis underpinning AF, implying potential implications for precisive prophylaxis and management of AF.


2021 ◽  
Vol 43 (3) ◽  
pp. 1977-1996
Author(s):  
Rongfan Wang ◽  
Fengqi Wu ◽  
Xianrong Xie ◽  
Cunyi Yang

Due to its fast deterioration, soybean (Glycine max L.) has an inherently poor seed vigor. Vigor loss occurring during storage is one of the main obstacles to soybean production in the tropics. To analyze the genetic background of seed vigor, soybean seeds of a recombinant inbred line (RIL) population derived from the cross between Zhonghuang24 (ZH24, low vigor cultivar) and Huaxia3hao (HX3, vigorous cultivar) were utilized to identify the quantitative trait loci (QTLs) underlying the seed vigor under −20 °C conservation and accelerated aging conditions. According to the linkage analysis, multiple seed vigor-related QTLs were identified under both −20 °C and accelerated aging storage. Two major QTLs and eight QTL hotspots localized on chromosomes 3, 6, 9, 11, 15, 16, 17, and 19 were detected that were associated with seed vigor across two storage conditions. The indicators of seed vigor did not correlate well between the two aging treatments, and no common QTLs were detected in RIL populations stored in two conditions. These results indicated that deterioration under accelerated aging conditions was not reflective of natural aging at −20 °C. Additionally, we suggest 15 promising candidate genes that could possibly determine the seed vigor in soybeans, which would help explore the mechanisms responsible for maintaining high seed vigor.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Simone Mozzachiodi ◽  
Lorenzo Tattini ◽  
Agnes Llored ◽  
Agurtzane Irizar ◽  
Neža Škofljanc ◽  
...  

AbstractHybrids between diverged lineages contain novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explore to what extent an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 Saccharomyces cerevisiae and S. paradoxus diploid hybrids with different genomic structures and levels of sterility. Genome analyses of 275 clones reveal that RTG promotes recombination and generates extensive regions of loss-of-heterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination is reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially arises in regions with low local heterozygosity and near meiotic recombination hotspots. The loss-of-heterozygosity has a profound impact on sexual and asexual fitness, and enables genetic mapping of phenotypic differences in sterile lineages where linkage analysis would fail. We propose that RTG gives sterile yeast hybrids access to a natural route for genome recombination and adaptation.


2021 ◽  
pp. jmedgenet-2021-107825
Author(s):  
Vanessa Luiza Romanelli Tavares ◽  
Sofia Ligia Guimarães-Ramos ◽  
Yan Zhou ◽  
Cibele Masotti ◽  
Suzana Ezquina ◽  
...  

BackgroundAuriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (PLCB4, GNAI3 and EDN1) and some cases remain unsolved. Here we studied a large unsolved four-generation family.MethodsWe performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells.ResultsThis study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9, which is located over 200 kb telomeric to the top candidate gene TWIST1. Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1, in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells.ConclusionOur findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype.


2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Guohong Cheng ◽  
Shichao Sun ◽  
Linlin Zhou ◽  
Guanzhong Wu

This study adopted smart card data collected from metro systems to identify city centers and illustrate how city centers interacted with other regions. A case study of Xi’an, China, was given. Specifically, inflow and outflow patterns of metro passengers were characterized to measure the degree of population agglomeration of an area, i.e., the centricity of an area. On this basis, in order to overcome the problem of determining the boundaries of the city centers, Moran’s I was adopted to examine the spatial correlation between the inflow and outflow of ridership of adjacent areas. Three residential centers and two employee centers were identified, which demonstrated the polycentricity of urban structure of Xi’an. With the identified polycenters, the dominant spatial connections with each city center were investigated through a multiple linkage analysis method. The results indicated that there were significant connections between residential centers and employee centers. Moreover, metro passengers (commuters mostly) flowing into the identified employee centers during morning peak-hours mainly came from the northern and western area of Xi’an. This was consistent with the interpretation of current urban planning, which validated the effectiveness of the proposed methods. Policy implications were provided for the transport sector and public transport operators.


2021 ◽  
pp. 105-168
Author(s):  
Susan H. Blanton
Keyword(s):  

2021 ◽  
Author(s):  
Jacob I Marsh ◽  
Haifei Hu ◽  
Jakob Petereit ◽  
Philipp E Bayer ◽  
Babu Valliyodan ◽  
...  

Here, we present association and linkage analysis of 985 wild, landrace and cultivar soybean accessions in a pan genomic dataset to characterize the major high-protein/low-oil associated locus cqProt-003 located on chromosome 20. A significant trait associated region within a 173 kb linkage block was identified and variants in the region were characterised, identifying 34 high confidence SNPs, 4 insertions, 1 deletion and a larger 304 bp structural variant in the high-protein haplotype. Trinucleotide tandem repeats of variable length present in the third exon of gene 20G085100 are strongly correlated with the high-protein phenotype and likely represent causal variation. Structural variation has previously been found in the same gene, for which we report the global distribution of the 304bp deletion and have identified additional nested variation present in high-protein individuals. Mapping variation at the cqProt-003 locus across demographic groups suggests that the high-protein haplotype is common in wild accessions (94.7%), rare in landraces (10.6%) and near absent in cultivated breeding pools (4.1%), suggesting its decrease in frequency primarily correlates with domestication and continued during subsequent improvement. However, the variation that has persisted in under-utilized wild and landrace populations holds high breeding potential for breeders willing to forego seed oil to maximise protein content. The results of this study include the identification of distinct haplotype structures within the high-protein population, and a broad characterization of the genomic context and linkage patterns of cqProt-003 across global populations, supporting future functional characterisation and modification.


2021 ◽  
Author(s):  
Tanja C. Nijboer ◽  
Ellen V.S. Hessel ◽  
Gijs W. van Haaften ◽  
Martine J. van Zandvoort ◽  
Peter J. van der Spek ◽  
...  

AbstractColour agnosia is a disorder that impairs colour knowledge (naming, recognition) despite intact colour perception. Previously, we have identified the first and only-known family with hereditary developmental colour agnosia. The aim of the current study was to explore genomic regions and candidate genes that potentially cause this trait in this family. For three family members with developmental colour agnosia and three unaffected family members CGH-array analysis and exome sequencing was performed, and linkage analysis was carried out using DominantMapper, resulting in the identification of 19 cosegregating chromosomal regions. Whole exome sequencing resulted in 11 rare coding variants present in all affected family members with developmental colour agnosia and absent in unaffected members. These variants affected genes that have been implicated in neural processes and functions (CACNA2D4, DDX25, GRINA, MYO15A), that have a indirect link to brain function or development (MAML2, STAU1, TMED3), and a remaining group lacking brain expression or involved in non-neural traits (DEPDC7, OR1J1, OR8D4, RABEPK). Although this is an explorative study, the small set of candidate genes that could serve as a starting point for unravelling mechanisms of higher level cognitive functions and cortical specialization, and disorders therein such as developmental colour agnosia.


2021 ◽  
Vol 51 ◽  
pp. e157
Author(s):  
Radosveta Bozhilova ◽  
Elena Chaparova ◽  
Ivan Popov ◽  
Olga Beltcheva ◽  
Christian Kostov ◽  
...  

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Poornima Vijayan ◽  
Saidah Hack ◽  
Tony Yao ◽  
Mohammad Azfar Qureshi ◽  
Andrew D. Paterson ◽  
...  

Abstract Background Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases. Many genetic causes have been identified in FSGS but even in families with comprehensive testing, a significant proportion remain unexplained. Methods In a family with adult-onset autosomal dominant FSGS, linkage analysis was performed in 11 family members followed by whole exome sequencing (WES) in 3 affected relatives to identify candidate genes. Results Pathogenic variants in known nephropathy genes were excluded. Subsequently, linkage analysis was performed and narrowed the disease gene(s) to within 3% of the genome. WES identified 5 heterozygous rare variants, which were sequenced in 11 relatives where DNA was available. Two of these variants, in LAMA2 and LOXL4, remained as candidates after segregation analysis and encode extracellular matrix proteins of the glomerulus. Renal biopsies showed classic segmental sclerosis/hyalinosis lesion on a background of mild mesangial hypercellularity. Examination of basement membranes with electron microscopy showed regions of dense mesangial matrix in one individual and wider glomerular basement membrane (GBM) thickness in two individuals compared to historic control averages. Conclusions Based on our findings, we postulate that the additive effect of digenic inheritance of heterozygous variants in LAMA2 and LOXL4 leads to adult-onset FSGS. Limitations to our study includes the absence of functional characterization to support pathogenicity. Alternatively, identification of additional FSGS cases with suspected deleterious variants in LAMA2 and LOXL4 will provide more evidence for disease causality. Thus, our report will be of benefit to the renal community as sequencing in renal disease becomes more widespread.


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