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Celiac disease is a common autoimmune disease caused by sensitivity to the dietary protein gluten. Forty loci have been implicated in the disease. All disease loci have been characterized as low-penetrance, with the exception of the high-risk genotypes in the HLA-DQA1 and HLA-DQB1 genes, which are necessary but not sufficient to cause the disease. The very strong effects from the known HLA loci and the genetically complex nature of the major histocompatibility complex (MHC) have precluded a thorough investigation of the region. The purpose of this study was to test the hypothesis that additional celiac disease loci exist within the extended MHC (xMHC). A set of 1898 SNPs was analyzed for association across the 7.6 Mb xMHC region in 1668 confirmed celiac disease cases and 517 unaffected controls. Conditional recursive partitioning was used to create an informative indicator of the known HLA-DQA1 and HLA-DQB1 high-risk genotypes that was included in the association analysis to account for their effects. A linkage disequilibrium-based grouping procedure was utilized to estimate the number of independent celiac disease loci present in the xMHC after accounting for the known effects. There was significant statistical evidence for four new independent celiac disease loci within the classic MHC region. This study is the first comprehensive association analysis of the xMHC in celiac disease that specifically accounts for the known HLA disease genotypes and the genetic complexity of the region.

Plant height is an important target for soybean breeding. It is a typical quantitative trait controlled by multiple genes and is susceptible to environmental influences. Here, we carried out phenotypic analysis of 156 recombinant inbred lines derived from “Dongnong L13” and “Henong 60” in nine environments at four locations over 6 years using interval mapping and inclusive composite interval mapping methods. We performed quantitative trait locus (QTL) analysis by applying pre-built simple-sequence repeat maps. We detected 48 QTLs, including nine significant QTLs detected by multiple methods and in multiple environments. Meanwhile, genotyping of all lines using the SoySNP660k BeadChip produced 54,836 non-redundant single-nucleotide polymorphism (SNP) genotypes. We used five multi-locus genome-wide association analysis methods to locate 10 quantitative trait nucleotides (QTNs), four of which overlap with previously located QTLs. Five candidate genes related to plant height are predicted to lie within 200 kb of these four QTNs. We identified 19 homologous genes in Arabidopsis, two of which may be associated with plant height. These findings further our understanding of the multi-gene regulatory network and genetic determinants of soybean plant height, which will be important for breeding high-yielding soybean.

Abstract Background The changing climate is altering timing of key fruit ripening processes and increasing the occurrence of fruit defects. To improve our understanding of the genetic control of raspberry fruit development an enhanced genetic linkage map was developed and used to examine ripening phenotypic data. Results In this study we developed an enhanced genetic linkage map for the raspberry cvs. Glen Moy x Latham reference mapping population using genotyping by sequencing (GbS). Alignment to a newly sequenced draft reference genome of red raspberry, cultivar (cv.) Glen Moy, identified 8019 single nucleotide polymorphisms (SNPs). After stringent filtering to take account of read coverage over all the progeny individuals, association with a single chromosome, heterozygosity and marker regression mapping, 2348 high confidence SNPs were retained and integrated with an existing raspberry genetic map. The linkage map contained many more SNPs segregating in Latham than in Glen Moy. This caused difficulties in quantitative trait loci (QTL) mapping with standard software and a novel analysis based on a hidden Markov model was used to improve the mapping. QTL mapping using the newly generated dense genetic map not only corroborated previously identified genetic locations but also provided additional genetic elements controlling fruit ripening in raspberry. Conclusion The high-density GbS map located the QTL peaks more precisely than in earlier studies, aligned the QTLs with Glen Moy genome scaffolds, narrowed the range of potential candidate genes to these regions that can be utilised in other populations or in gene expression studies to confirm their role and increased the repertoire of markers available to understand the genetic control of fruit ripening traits.

Abstract Background Tensin2 is a focal adhesion-localized multidomain protein expressed in various tissues, and its dysfunction leads to alterations in podocytes. However, these podocyte-related manifestations are dependent on murine strain. Tensin2 dysfunction results in susceptible strains developing podocyte foot process effacement and massive albuminuria, whereas podocytes in resistant strains remain almost intact. In our previous studies, quantitative trait loci analysis and congenic analysis using resistant C57BL/6J and susceptible ICGN mice identified a modifier locus associated with podocyte injury caused by tensin2 dysfunction on chromosome 2. However, the effect of this modifier locus on chromosome 2 is insufficient to explain the resistance of C57BL/6J mice to tensin2 dysfunction, indicating the existence of other modifier genes. Results Whereas previous studies focused on the severity of chronic kidney disease, the present study focused on podocyte injury. We performed a genome-wide linkage analysis of backcrosses between two tensin2-deficient mouse strains, B6.ICGN-Tns2 nph and FVB.ICGN-Tns2 nph , and detected a novel major modifier locus on chromosome 10. The combined effect of the C57BL/6J alleles of the two loci on chromosomes 2 and 10 reduced the urinary albumin excretion caused by tensin2 dysfunction to a level comparable to that of C57BL/6J mice. Conclusions These data indicate that the resistance to podocyte injury caused by tensin2 dysfunction is mainly produced by the effects of the modifier genes on the two loci. The identification of these modifier genes is expected to help elucidate the mechanism underlying podocyte injury.

Abstract Introduction Less than 10% of early‐onset Alzheimer's disease (EOAD) is explained by known mutations. Methods We conducted genetic linkage analysis of 68 well‐phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in APP, PSEN1, and PSEN2 and with two or more individuals with EOAD. Results We identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late‐onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ∼3 Mb upstream of the ceroid lipofuscinosis 3 (CLN3) gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein. Discussion This study supports the notion that the genetic architectures of unexplained EOAD and late‐onset AD overlap partially, but not fully.

Polydactyly and syndactyly are digital abnormalities in limb‐associated birth defects usually caused by genetic disorders. In this study, a five‐generation Chinese pedigree was found with triphalangeal thumb polysyndactyly syndrome (TPTPS), showing an autosomal dominant pattern of inheritance. We utilized linkage analysis and whole genome sequencing (WGS) for the genetic diagnosis of this pedigree. Linkage analysis was performed using a genome‐wide single nucleotide polymorphism (SNP) chip and three genomic regions were identified in chromosomes 2, 6, and 7 with significant linkage signals. WGS discovered a copy number variation (CNV) mutation caused by a large duplication region at the tail of chromosome 7 located in exons 1–5 of the LMBR1 gene, including the zone of polarizing activity regulatory sequence (ZRS), with a length of approximately 180 kb. A real‐time polymerase chain reaction (PCR) assay confirmed the duplication. The findings of our study supported the notion that large duplications including the ZRS caused TPTPS. Our study showed that linkage analysis in combination with WGS could successfully identify the disease locus and causative mutation in TPTPS, which could help elucidate the molecular mechanisms and genotype–phenotype correlations in polydactyly. [ABSTRACT FROM AUTHOR]

Preimplantation genetic diagnosis (PGD) of genetic diseases, combined with human leukocyte antigen (HLA) typing (PGD‐HLA), is a useful technique to have healthy offspring that are compatible with a sibling for hematopoietic stem cells transplantation (HSCT) to treat their genetic diseases. Here, we report a new strategy using single nucleotide polymorphism (SNP) linkage analysis for monogenic disease PGD combined with HLA typing, to simultaneously obtain the information of chromosomal aneuploidy, target mutations and HLA typing through a single low‐depth next generation sequencing (NGS) procedure. In this study, five couples with probands underwent SNP linkage analysis for PGD‐HLA typing were recruited. Within these five couples, two couples fortunately harvested four unaffected and HLA matched embryos with their siblings. After embryo transfer, two healthy neonates were born successfully. Subsequently, cord blood hematopoietic stem cells obtained from these two neonates were collected and frozen for treating their sick siblings. This novel strategy could provide abundant and specific SNPs for each family, therefore linkage information adjacent and even within HLA clusters were apparent. This study offers a highly flexible and precise method which could eliminate misdiagnosis caused by chromosomal recombination of the HLA gene, thus potentially benefit the success rate of HSCT. [ABSTRACT FROM AUTHOR]

Background: The genetics of resistance to loose smut of wheat (Triticum aestivum L.) caused by the fungus Ustilago tritici (Pers.) Rostr. is not well understood. This study examines loose smut resistance in Sonop (TD-14), a South African spring wheat variety. A doubled haploid (DH) population of 163 lines derived from the cross Diamont/TD-14 was studied. The parents and progenies were inoculated with U. tritici races T2, T9, and T39 individually in growth facilities at Morden and Swift Current, Canada. Loose smut incidence (LSI) and partial loose smut resistance (PLSR) were assessed. Results: A whole genome linkage map was developed consisting of 11,519 SNP loci found on 31 linkage groups spanning 2845 cM. A new major resistance gene Ut11 was located to the distal end of chromosome arm 7BS. Ut11 conferred resistance to U. tritici race T2, but not races T9 and T39. Quantitative trait locus (QTL) mapping identified four QTL controlling LSI in the Diamont/TD-14 DH population on chromosomes 3B, 4B, 5B, and 7B (at Ut11) with TD-14 contributing the resistance alleles at three of these loci. The major QTL QUt.mrc-5B was effective against all three races and explained up to 81% of the phenotypic variation. The only QTL identified for PLSR coincided with the LSI QTL QUt.mrc-5B indicating that this locus affected both loose smut incidence and partial smutting of spikes. Conclusions: A race-specific resistance gene Ut11 and a broadly effective resistance QTL QUt.mrc-5B were the main loci controlling loose smut resistance in the differential line TD-14 (cultivar Sonop). This study provides insight into the genetics of loose smut resistance in spring wheat Sonop and the single nucleotide polymorphism (SNP) markers linked to the resistance gene Ut11 and QTL QUt.mrc-5B will be useful for selecting loose smut resistance in breeding programs. [ABSTRACT FROM AUTHOR]

Pod number is an important component of yield in soybean (Glycine max (L.) Merr.), and pods are unevenly distributed in the upper, middle and lower parts of the plant. Here, linkage analysis combined with genome-wide association study (GWAS) was used to identify 20 pod number-related traits in four-way recombinant inbred lines (FW-RILs) derived from crosses between the four soybean varieties (Kenfeng 14 × Kenfeng 15) × (Heinong 48 × Kenfeng 19). The results show that pod number-related traits are highly influenced by genetic factors, while the environment plays only a minor role. A total of 602 QTLs were identified, of which 52 were detected in multiple environments (over two environments). In addition, GWAS detected 26 common QTNs (identified by multiple methods or environments) in the QTL intervals. Based on gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, 11 potential candidate genes were identified that likely involved the growth and development of soybean pods. These findings will help elucidate the genetic basis of pod number traits. [ABSTRACT FROM AUTHOR]

In order to map quantitative trait loci (QTLs) for allometries of body compositions and metabolic traits in chicken, we phenotypically characterize the allometric growths of multiple body components and metabolic traits relative to BWs using joint allometric scaling models and then establish random regression models (RRMs) to fit genetic effects of markers and minor polygenes derived from the pedigree on the allometric scalings. Prior to statistically inferring the QTLs for the allometric scalings by solving the RRMs, the LASSO technique is adopted to rapidly shrink most of marker genetic effects to zero. Computer simulation analysis confirms the reliability and adaptability of the so-called LASSO-RRM mapping method. In the F2 population constructed by multiple families, we formulate two joint allometric scaling models of body compositions and metabolic traits, in which six of nine body compositions are tested as significant, while six of eight metabolic traits are as significant. For body compositions, a total of 14 QTLs, of which 9 dominant, were detected to be associated with the allometric scalings of drumstick, fat, heart, shank, liver and spleen to BWs; while for metabolic traits, a total of 19 QTLs also including 9 dominant be responsible for the allometries of T4, IGFI, IGFII, GLC, INS, IGR to BWs. The detectable QTLs or highly linked markers can be used to regulate relative growths of the body components and metabolic traits to BWs in marker-assisted breeding of chickens. [ABSTRACT FROM AUTHOR]

Many lethal mutations of the silkworm egg have been reported. The lethal phenotype is exhibited at several stages including blastokinesis, head pigmentation, and body pigmentation. We recently isolated a novel lethal mutant, which the skin color of the mature embryo became a light orange and the embryo died before hatching. In this study, we performed morphological observation and genetic analysis of this lethal mutation. Phenotypic observation showed that the phenotype of this lethal mutant is quite similar to that of the sex-linked chocolate lethal (schl), chocolate (ch), chocolate 2 (ch-2), and maternal chocolate (cm) mutants. We first performed the crossing experiment, which revealed that this mutation is regulated by a single recessive gene, and is not linked to the sex chromosome on which the schl mutation is located. We next performed the pre-linkage test with this lethal mutation and three other mutations, which revealed that an allelic relationship among these mutations could not be detected. Therefore, we determined that this is a novel lethal mutant, which we named light orange lethal (l-og). We next performed the linkage analysis of the l-og mutation using 20 F2 individuals and primer sets designed for each chromosome. The linkage analysis revealed that the l-og mutation is definitely located on chromosome 10. Furthermore, the rough mapping using 119 F2 individuals and 7 primer sets designed for chromosome 10 revealed that the l-og-linked region was narrowed down to approximately 3.7 Mb long on chromosome 10. [ABSTRACT FROM AUTHOR]

Background: Curd architecture is one of the most important characters determining the curd morphology of cauliflower. However, the genetic mechanism dissection of this complex trait at molecular level is lacking. Genes/QTLs responsible for the morphological differences between present-day loose-curd and compact-curd cauliflower haven't been well revealed. Results: Herein, by using a common compact-curd parent and two loose-curd parents, we developed two double haploid (DH) populations including 122 and 79 lines, respectively. For each population, we decomposed the curd architecture concept into four parameters (basal diameter, stalk length, stalk angle and curd solidity), and collected corresponding phenotypic data for each parameter across two environments. The Kosambi function and composite interval mapping algorithm were conducted to construct the linkage map and analyze the QTLs associated with curd architecture parameters. A total of 20 QTLs were detected with the minimum likelihood of odd (LOD) values ranging from 2.61 to 8.38 and the percentage of the phenotypic variance explained by each QTL (PVE) varying between 7.69 and 25.10%. Of these, two QTLs controlling stalk length (qSL.C6–1, qSL.C6–2) and two QTLs controlling curd solidity (qCS.C6–1 and qCS.C6–2) were steadily expressed in both environments. Further, qSL.C6–1, qSL.C6–2, qCS.C6–1 and qCS.C6–4 fell into the same chromosomal region of the reference genome, indicating that these loci are involved in pleiotropic effects or are tightly linked. Conclusion: The current study identified a series of QTLs associated with curd architecture parameters, which might contribute essentially to the formation of present-day loose-curd cauliflower that is widely cultivated in China. These results may pave the way for intensive deciphering the molecular mechanisms of curd development and for marker-assisted selection of curd morphology in cauliflower breeding. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a complex disorder for which the majority of the underlying germline predisposition factors remain still unidentified. Here, we combined whole‐exome sequencing (WES) and linkage analysis in families with multiple relatives affected by CRC to identify candidate genes harboring rare variants with potential high‐penetrance effects. Forty‐seven affected subjects from 18 extended CRC families underwent WES. Genome‐wide linkage analysis was performed under linear and exponential models. Suggestive linkage peaks were identified on chromosomes 1q22–q24.2 (maxSNP = rs2134095; LODlinear = 2.38, LODexp = 2.196), 7q31.2–q34 (maxSNP = rs6953296; LODlinear = 2.197, LODexp = 2.149) and 10q21.2–q23.1 (maxSNP = rs1904589; LODlinear = 1.445, LODexp = 2.195). These linkage signals were replicated in 10 independent sets of random markers from each of these regions. To assess the contribution of rare variants predicted to be pathogenic, we performed a family‐based segregation test with 89 rare variants predicted to be deleterious from 78 genes under the linkage intervals. This analysis showed significant segregation of rare variants with CRC in 18 genes (weighted p‐value > 0.0028). Protein network analysis and functional evaluation were used to suggest a plausible candidate gene for germline CRC predisposition. Etiologic rare variants implicated in cancer germline predisposition may be identified by combining traditional linkage with WES data. This approach can be used with already available NGS data from families with several sequenced members to further identify candidate genes involved germline predisposition to disease. This approach resulted in one candidate gene associated with increased risk of CRC but needs evidence from further studies. What's new? Inherited genetic factors are thought to account for more than one‐third of colorectal cancer (CRC) cases. Most predisposing genetic factors, however, remain unidentified. Here, genome‐wide linkage analysis using whole‐exome sequencing (WES) data was performed in families with marked CRC aggregation. The combined linkage‐sequencing approach identified possible linkage peaks on chromosomes 1q22‐q24.2, 7q31.2‐q34, and 10q21.2‐q23.1. Analyses of potentially pathogenic variants revealed significant segregation of rare variants in 18 genes, while functional analyses identified a plausible candidate gene for germline CRC predisposition. The findings underscore the utility of linkage analysis employing WES for the discovery of candidate genes for disease predisposition. [ABSTRACT FROM AUTHOR]

Plant height is an important target for soybean breeding. It is a typical quantitative trait controlled by multiple genes and is susceptible to environmental influences. Here, we carried out phenotypic analysis of 156 recombinant inbred lines derived from "Dongnong L13" and "Henong 60" in nine environments at four locations over 6 years using interval mapping and inclusive composite interval mapping methods. We performed quantitative trait locus (QTL) analysis by applying pre-built simple-sequence repeat maps. We detected 48 QTLs, including nine significant QTLs detected by multiple methods and in multiple environments. Meanwhile, genotyping of all lines using the SoySNP660k BeadChip produced 54,836 non-redundant single-nucleotide polymorphism (SNP) genotypes. We used five multi-locus genome-wide association analysis methods to locate 10 quantitative trait nucleotides (QTNs), four of which overlap with previously located QTLs. Five candidate genes related to plant height are predicted to lie within 200 kb of these four QTNs. We identified 19 homologous genes in Arabidopsis, two of which may be associated with plant height. These findings further our understanding of the multi-gene regulatory network and genetic determinants of soybean plant height, which will be important for breeding high-yielding soybean. [ABSTRACT FROM AUTHOR]

Infantile neuroaxonal dystrophy (INAD) is a rare, lethal, autosomal recessive neurodegenerative disease and leads to progressive impairment of movement and cognition. A couple with a proband child with calcium-independent group VI phospholipase A2 (PLA2G6)-associated INAD and a previous affected pregnancy sought pre-implantation genetic diagnosis (PGD) to bear a healthy child. Intracytoplasmic sperm injection treatment was performed and 15 blastocystic embryos were obtained at days 5 and 6, and these biopsies were amplified. PGD was performed by next-generation sequencing-based linkage analysis in conjunction with aneuploidy screening. Only two embryos were considered for transfer. In the second frozen-thawed embryo transfer cycle, transfer of a mosaic PLA2G6 c.692G>T heterozygous embryo resulted in a singleton ongoing pregnancy. Prenatal diagnosis was performed using amniotic fluid cells, providing results consistent with those of PGD. The aneuploidy screen and karyotype analysis indicated that the chromosomes of the fetus were normal without any mosaicism. The present study reported the first successful PGD for INAD. For parents at risk, this strategy may successfully lead to pregnancies with embryos unlikely to develop INAD, thus providing valuable experience in reproductive management regarding INAD and potentially other single-gene disorders. [ABSTRACT FROM AUTHOR]

Objectives: Bipolar disorder (BD) is a neuropsychiatric disorder with a complex pattern of inheritance. Although many genetic studies have been conducted on BD, its genetic correlates remain uncertain. This study was aimed at identifying the genetic underpinnings of the disorder in an Indian family, which has been under comprehensive clinical evaluation and follow‐up for over 12 years. Methods: We analysed a four‐generation family with several of its members diagnosed for BD employing a combination of genetic linkage and exome analysis. Results: We obtained suggestive LOD score for a chromosome 1 and a chromosome 6 marker (D1S410; LOD = 3.01, Ө = 0; and D6S289; LOD = 1.58, Ө = 0). Manual haplotyping of the regions encompassing these two markers helped delimit a critical genomic interval of 32.44 Mb (D1S2700‐D1S435; chromosome 1p31.1‐13.2) and another of 10.34 Mb (D6S470‐D6S422; chromosome 6p22.3‐22.2). We examined the exomic sequences corresponding to these two intervals and found rare variants, NM_181712.4: c.2461G>T (p.Asp821Tyr) in KANK4 at 1p31.1‐13.2; and NM_006366:c.‐93G>A, in the 5' UTR of CAP2 at 6p22.3‐22.2. Conclusions: Our studysuggests involvement of KANK4 or CAP2 or both in BD in this family. Further analysis of these two genes in BD patients and functional evaluation of the allelic variants identified are suggested. [ABSTRACT FROM AUTHOR]

To provision the world sustainably, modern society must increase overall crop production, while conserving and preserving natural resources. Producing more with diminishing water resources is an especially daunting endeavor. Toward the goal of genetically improving drought resilience of cultivated Upland cotton (Gossypium hirsutum L.), this study addresses the genetics of differential yield components referred to as productivity and fiber quality traits under regular-water versus low-water (LW) field conditions. We used ten traits to assess water stress deficit, which included six productivity and four fiber quality traits on two recombinant inbred line (RIL) populations from reciprocally crossed cultivars, Phytogen 72 and Stoneville 474. To facilitate genetic inferences, we genotyped RILs with the CottonSNP63K array, assembled high-density linkage maps of over 7000 SNPs and then analyzed quantitative trait variations. Analysis of variance revealed significant differences for all traits (p < 0.05) in these RIL populations. Although the LW irrigation regime significantly reduced all traits, except lint percent, the RILs exhibited a broad phenotypic spectrum of heritable differences across the water regimes. Transgressive segregation occurred among the RILs, suggesting the possibility of genetic gain through phenotypic selection for drought resilience and perhaps through marker-based selection. Analyses revealed more than 150 quantitative trait loci (QTLs) associated with productivity and fiber quality traits (p < 0.005) on different genomic regions of the cotton genome. The multiple-QTL models analysis with LOD > 3.0 detected 21 QTLs associated with productivity and 22 QTLs associated with fiber quality. For fiber traits, strong clustering and QTL associations occurred in c08 and its homolog c24 as well as c10, c14, and c21. Using contemporary genome sequence assemblies and bioinformatically related information, the identification of genomic regions associated with responses to plant stress/drought elevates the possibility of using marker-assisted and omics-based selection to enhance breeding for drought resilient cultivars and identifying candidate genes and networks. RILs with different responses to drought indicated that it is possible to maintain high fiber quality under LW conditions or reduce the of LW impact on quality. The heritable variation among elite bi-parental RILs for productivity and quality under field drought conditions, and their association of QTLs, and thus specific genomic regions, indicate opportunities for breeding-based gains in water resource conservation, i.e., enhancing cotton's agricultural sustainability. [ABSTRACT FROM AUTHOR]

Atherosclerosis develops with age and is partially controlled by genetics. Research to date has identified common variants with small effects on atherosclerosis related traits. We aimed to use family-based genome-wide linkage analysis to identify chromosomal regions potentially harboring rare variants with larger effects for atherosclerosis related traits. Participants included 2205 individuals from the Long Life Family Study (LLFS), which recruited families with exceptional longevity from Boston, New York, Pittsburgh, and Denmark. Participants underwent B-mode ultrasonography of the carotid arteries to measure intima-media thickness (IMT), inter-adventitial diameter (IAD), and plaque presence and severity. We conducted residual heritability and genome-wide linkage analyses adjusted for age, age2, sex, and field center using pedigree-based maximum-likelihood methods in SOLAR. All carotid traits were significantly heritable with a range of 0.68 for IAD to 0.38 for IMT. We identified three chromosomal regions with linkage to IAD (3q13; max LOD 5.3), plaque severity (17q22-q23, max LOD 3.2), and plaque presence (17q24, max LOD 3.1). No common allelic variants within these linkage peaks were associated with the carotid artery traits. We identified three chromosomal regions with evidence of linkage to carotid artery diameter and atherosclerotic plaque in exceptionally long-lived families. Since common allelic variants within our linkage peaks did not account for our findings, future follow-up resequencing of these regions in LLFS families should help advance our understanding of atherosclerosis, CVD, and healthy vascular aging. Image 1 • Measures of carotid atherosclerosis assessed via ultrasound were significantly heritable. • We identified 3 discrete chromosomal regions with significant linkage to carotid atherosclerosis. • These regions contain genes with previous evidence of association with atherosclerotic traits. • Common SNPs in these regions were not associated with atherosclerosis; thus, these families may harbor rare genetic variants. [ABSTRACT FROM AUTHOR]

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Average arterial oxyhemoglobin saturation during sleep (AvSpO 2 S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, 1,2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO 2 S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10−7). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO 2 S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO 2 S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO 2 S. [ABSTRACT FROM AUTHOR]

Palmoplantar keratoderma (PPK) is a heterogenous group of skin disorders characterized by a persistent thickening of the palms of the hands and sometimes soles of the feet. PPK can be classified into many types, including diffuse, transgradient, and focal or striate, where the areas of palmoplantar skin are alternatively thickened. Mutations in four main genes, keratin 9 (KRT9), keratin 1 (KRT1), desmoglein (DSG1), and desmoplakin (DSP), have been associated with PPK. Striate PPK (SPPK) is commonly caused by mutations in DSG1. However, DSP and KRT1 gene mutations have been identified in some cases. In this study, fragment and sequencing analysis were performed for a large Syrian family with dominant SPPK. Segregation analysis showed a linkage with DSG1 gene. Direct Sanger sequencing identified a new mutation c.dup165_168AGCA. This frameshift mutation was heterozygous in all affected family members and absent in all normal individuals. [ABSTRACT FROM AUTHOR]

Hybrid lethality, a postzygotic mechanism of reproductive isolation, is a phenomenon that causes the death of F1 hybrid seedlings. Hybrid lethality is generally caused by the epistatic interaction of two or more loci. In the genus Nicotiana, N. debneyi has the dominant allele Hla1-1 at the HLA1 locus that causes hybrid lethality in F1 hybrid seedlings by interaction with N. tabacum allele(s). Here, we mapped the HLA1 locus using the F2 population segregating for the Hla1-1 allele derived from the interspecific cross between N. debneyi and N. fragrans. To map HLA1, several DNA markers including random amplified polymorphic DNA, amplified fragment length polymorphism, and simple sequence repeat markers, were used. Additionally, DNA markers were developed based on disease resistance gene homologs identified from the genome sequence of N. benthamiana. Linkage analysis revealed that HLA1 was located between two cleaved amplified polymorphic sequence markers Nb14-CAPS and NbRGH1-CAPS at a distance of 10.8 and 10.9 cM, respectively. The distance between these markers was equivalent to a 682 kb interval in the genome sequence of N. benthamiana.

Objectives: Bipolar disorder (BD) is characterized by manic and depressive states that onset at various times in life. Research shows that early onset forms of BD are associated with a stronger genetic loading for the illness. We hypothesized that using age at onset to look at subsets of BD families in a genetic linkage analysis would prove useful in separating etiologically homogeneous BD sub-groups and subsequently identifying genetic susceptibility regions. Methods: We used the wave-I National Institute of Mental Health (NIMH) Genetics Initiative BD sample, which includes 540 individuals from 97 families with BD, in an ordered-subsets linkage analysis with age at onset of mania as the subset-identifying covariate. This analysis was performed using GENEHUNTER-PLUS followed by the ordered-subsets analysis program. This program generates empirical p-values for the subset with the largest LOD score to determine whether this value was significantly higher than the baseline LOD score using all families. Results: Three chromosomal regions resulted in LOD scores above 2.0: 2.21 (6q25), 3.21 (9q34), and 2.16 (20q11). The largest increase in LOD score was observed on chromosome 9q34 between markers D9S290 and D9S915 in the subset of 58 families that had mania onset before age 20. Families with a minimal mania onset less than 20 years had a significantly greater number of psychiatric comorbidities (p = 0.02) and a marginal increase in depressive symptoms (p = 0.10). Conclusions: Further investigation into chromosomal region 9q34 is necessary to determine whether this region may harbor a gene specific to families with a minimal age at onset of less than 20.

The additive genetic gamma frailty model has been proposed for genetic linkage analysis for complex diseases to account for variable age of onset and possible covariates effects. To avoid ascertainment biases in parameter estimates, retrospective likelihood ratio tests are often used, which may result in loss of efficiency due to conditioning. This paper considers when the sibships are ascertained by having at least two affected sibs with the disease before a given age and provides two approaches for estimating the parameters in the additive gamma frailty model. One approach is based on the likelihood function conditioning on the ascertainment event, the other is based on maximizing a full ascertainment-adjusted likelihood. Explicit forms for these likelihood functions are derived. Simulation studies indicate that when the baseline hazard function can be correctly pre-specified, both approaches give accurate estimates of the model parameters. However, when the baseline hazard function has to be estimated simultaneously, only the ascertainment-adjusted likelihood method gives an unbiased estimate of the parameters. These results imply that the ascertainment-adjusted likelihood ratio test in the context of the additive genetic gamma frailty may be used for genetic linkage analysis.

Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb. In one family, a deletion at marker D7S630 was complex, with two segments deleted (37 kb and 18 kb) and two retained (2,836 bp and 38 bp). Three families had deletions at D7S517, with each family having a different deletion (96 kb, 183 kb, and >69 kb). Another three families had deletions at D8S264, again with each family having a different deletion, ranging in size from 260 kb. At a fourth marker, D8S272, a 192-kb deletion was found in five families. Unrelated subjects and additional families without autism were screened for deletions at these four sites. Families screened included 40 families from Centre d'Etude du Polymorphisme Humaine and 28 families affected with learning disabilities. Unrelated samples were 299 elderly control subjects, 121 younger control subjects, and 248 subjects with Alzheimer disease. The deletion allele at D8S272 was found in all populations screened. For the other three sites, no additional deletions were identified in any of the groups without autism. Thus, these deletions appear to be specific to autism kindreds and are potential autism-susceptibility alleles. An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis.

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of polyneuropathies characterized by degeneration of peripheral nerves, resulting in distal muscle atrophy, sensory loss, and deformities of hands and feet. We have studied 34 individuals in a large 84-member four-generation central Illinois family with autosomal dominant Charcot-Marie-Tooth and deafness. Nerve conduction velocities are consistent with type 1 CMT. Audiological evaluation revealed both auditory neuropathy and cochlear involvement in affected individuals. There is increasing clinical severity and younger age of onset of CMT and deafness with each progressive generation, suggestive of anticipation (P < 0.05). The proband, a female diagnosed at birth with hypotonia, bilateral vocal cord palsy, swallowing incoordination, and hearing impairment, died at age 18 months. Another individual died at the age of 3 months from hypotonia later attributed to CMT. Genetic analysis indicated that affected individuals in this family do not have the common 1.4 Mb duplication associated with type 1A CMT; however, all affected individuals have a unique G to C transversion at position 248 in coding exon 3 of the peripheral myelin PMP22 gene located on chromosome 17p11.2-p12. This mutation is predicted to cause an Ala67Pro substitution in the second transmembrane domain of PMP22, consistent with the molecular cause of the CMT phenotype. However, it does not explain the cochlear component of the deafness, the clinical observation of anticipation, and other features in this family.

Abstract Background Combining ability is a measure for selecting elite parents that make the highest contributions to hybrid performance. However, the genetic bases of combining ability and how they contributed to heterosis is seldomly known. Results We constructed a both NCII and NCIII population derived from an indica-japonica cross to study the relationship among parental performance, combining ability and hybrid performance of 11 agronomic traits. Among them, specific combining ability is more important to grain yield than parental performance and general combining ability. We performed linkage analyses to phenotypic values and combining ability of all 11 traits in Doubled haploid lines and its two backcross populations and identified 108 QTLs in total. Among these QTLs, four known loci, Sd1, Ghd7, Ghd8 and DEP1 contribute a lot to GCA effects of agronomic traits except grain yield and seed setting rate. Three QTLs, Ghd8, S5 and qS12, contribute a lot to SCA effects of grain yield and present overdominace. Conclusions Our study provides insights into the genetic bases of combining ability and heterosis and will promote the improvements of indica-japonica hybrid breeding.

Objective(s): Mutations in the UGT1A1 gene are responsible for hyperbilirubinemia syndromes including Crigler-Najjar type 1 and 2 and Gilbert syndrome. In view of the genetic heterogeneity and involvement of large numbers of the disease causing mutations, the application of polymorphic markers in the UGTA1 gene could be useful in molecular diagnosis of the disease. Materials and Methods: In the present study, two polymorphic markers including rs4148326 and rs4124874 in the UGT1A1 gene region were characterized. The markers were selected using bioinformatics analysis of the UGT1A1 gene region and genotyped in 212 unrelated healthy individuals and 13 family trios in the Iranian population using Tetra-Primer ARMS PCR technique. The allele frequency and population status of the alleles were estimated using GENEPOP, FBAT, PowerMarker and Arlequin software. Results: The results indicated that in the case of rs4148326 marker, allele frequency for T and C allele was 66.04% and 33.96%, respectively. For rs4124874 marker, allele frequency for G and T alleles was 39.4% and 60.6%, respectively. The values of heterozygosity index for the markers examined were 64.1 for rs4148326 and 72.1 for rs4124874, respectively. The haplotype estimation analysis of the markers resulted in three informative haplotypes with frequencies ≥0.05. Moreover, the results suggested the presence of linkage disequilibrium between two markers. Conclusion: Altogether, the data suggested that rs4148326 and rs4124874 could be introduced as informative markers for molecular diagnosis of Crigler-Najjar type 1 and 2 and Gilbert syndrome in the Iranian population.

AIM: To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in PITX2 in the family. METHODS: Patients presented with typical ARS from a Chinese family were investigated. We performed genome-wide linkage scan and exome sequencing to identify the pathogenic mutations. Candidate mutations were verified for co-segregation in the whole pedigree using Sanger sequencing. Real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to verify the expression of the pathogenic gene. RESULTS: Genome-wide linkage and exome sequencing analyses showed PITX2 as the disease candidate gene. A>G substitution at position -11 of 3’ss of exon 5 (IVS5-11A>G) that co-segregated with the disease phenotype was discovered in the family. The PITX2 messenger ribonucleic acid and protein levels were about 50% lower in patients with ARS than in unaffected family members in the family. CONCLUSION: Our findings implicate the first intronic mutation of the PITX2 gene in the pathogenesis of a severe form of ARS in a Chinese family. This study highlights the importance of a systematic search for intronic mutation in ARS cases for which no mutations in the exons of PITX2 have been found.

PurposeTo perform linkage analysis of candidate loci in a large Midwestern family with autosomal dominant essential tremor.MethodsThirty-eight members of a six-generation family were evaluated for essential tremor using consensus criteria. Linkage analysis was performed with microsatellite markers reported for three genetic loci associated with familial essential tremor.ResultsPatients exhibited a combination of postural and kinetic tremor involving primarily the arms and hands, with a mean age of onset of 31 years. Genetic studies excluded linkage to ETM1 and ETM2 loci, as well as a candidate locus for parkinsonism and postural tremor on chromosome 4p.ConclusionFamilial essential tremor is a common hereditary movement disorder demonstrating phenotypic variability and genetic heterogeneity.

To analyze genetic linkage and map purple gene (BrPur) controlling purple inner leaves trait of Chinese cabbage, a F2 population was constructed by selfing a F1 plant from homozygous purple heading line ‘14S839’ and homozygous orange heading line ‘14S162’. The phenotype investigation of head color showed that the segregation ratio of purple to non-purple individuals was consistent with the expected ratio of 3:1, which indicated that purple inner leaves trait is controlled by a single dominant gene. A total of 297 SSRs in whole genome of Chinese cabbage were tested by modified Bulked Segregant Analysis (BSA) method. Two linked markers flanking BrPur, A710 and A714, were obtained and BrPur was mapped on linkage group A07 based on the sequence of these two markers. Subsequently, two new markers flanking BrPur, CL-12 and B214-87, were developed based on two known anthocyanins-related genes, Br4CL3 and Bra004214. Genetic mapping of all markers in the F2 mapping population showed CL-12 and B214-87 linked to BrPur with the genetic distance of 3.1 cM and 3.5 cM, respectively.

Importance: Autophagy is a process used by cells to recycle organelles and macromolecules and to eliminate intracellular pathogens. Previous studies have shown that some stains of Toxoplasma gondii are resistant to autophagy-dependent growth restriction, while others are highly susceptible. Although it is known that autophagy-mediated control requires activation by interferon gamma, the basis for why parasite strains differ in their susceptibility is unknown. Our findings indicate that susceptibility involves at least five unlinked parasite genes on different chromosomes, including several secretory proteins targeted to the parasite-containing vacuole and exposed to the host cell cytosol. Our findings reveal that susceptibility to autophagy-mediated growth restriction relies on differential recognition of parasite proteins exposed at the host-pathogen interface, thus identifying a new mechanism for cell-autonomous control of intracellular pathogens., Competing Interests: The authors declare no conflict of interest.

Genetic mapping is the determination of the position and relative genetic distance between genes or molecular markers in the chromosomes of a particular species. The construction of genetic maps uses data from the genotyping of the mapping population. Among the different mapping populations used, two are relatively common: the F 2 and recombinant inbred lines (RILs) obtained as a result of the controlled crossing of genetically diverse parental forms (e.g., inbred lines). Also, the dihaploid (DH) population is often used in plants, but obtaining DHs in different crops, including rye, is very difficult or even impossible. Any molecular marker system can be used for genotyping. Polymorphic markers are used for linkage analysis, differentiating parental forms with segregation in the mapping population, consistent with the appropriate single-gene model. A genetic map is a great source of information on a species and can be an exquisite tool for analyzing important quantitative traits (QT).This chapter presents the procedure of genetic map construction with two different algorithms using the JoinMap5.0 program. First, the Materials section briefly informs about the mapping program, showing how to obtain a mapping population and prepare data for mapping. Finally, the Methods section describes the protocol for the mapping procedure itself., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Immunoglobulin A (IgA) nephropathy (IgAN), the most common form of glomerulonephritis, is one of the leading causes of end-stage kidney disease (ESKD). It is widely believed that genetic factors play a significant role in the development of IgAN. Previous studies of IgAN have provided important insights to unravel the genetic architecture of IgAN and its potential pathogenic mechanisms. The genome-wide association studies (GWASs) together have identified over 30 risk loci for IgAN, which emphasizes the importance of IgA production and regulation in the pathogenesis of IgAN. Follow-up fine-mapping studies help to elucidate the candidate causal variant and the potential pathogenic molecular pathway and provide new potential therapeutic targets. With the rapid development of next-generation sequencing technologies, linkage studies based on whole-genome sequencing (WGS)/whole-exome sequencing (WES) also identify rare variants associated with IgAN, accounting for some of the missing heritability. The complexity of pathogenesis and phenotypic variability may be better understood by integrating genetics, epigenetics, and environment. We have compiled a review summarizing the latest advancements in genetic studies on IgAN. We similarly summarized relevant studies examining the involvement of epigenetics in the pathogenesis of IgAN. Future directions and challenges in this field are also proposed.

Crime linkage has been the subject of increasing attention in academic research. Research has found support for the principles of behavioural consistency and distinctiveness, which underpin crime linkage, but this does not provide direct evidence as to whether crime linkage is useful in practice. This literature review draws together documentation that refers to the practice of crime linkage, from assessing analysts' efficacy, to discussing the usage of computerised tools to assist with the linkage process, to providing a comprehensive outline of the process itself. The implications of the amount and type of information currently available are discussed, including the variations in practice and terminology that were explored. Avenues for future investigation and the manner in which future research could be conducted are set out in a research agenda. [ABSTRACT FROM AUTHOR]

Gene expression is subject to stochastic noise, but to what extent and by which means such stochastic variations are coordinated among different genes are unclear. We hypothesize that neighboring genes on the same chromosome co-fluctuate in expression because of their common chromatin dynamics, and verify it at the genomic scale using allele-specific single-cell RNA-sequencing data of mouse cells. Unexpectedly, the co-fluctuation extends to genes that are over 60 million bases apart. We provide evidence that this long-range effect arises in part from chromatin co-accessibilities of linked loci attributable to three-dimensional proximity, which is much closer intra-chromosomally than inter-chromosomally. We further show that genes encoding components of the same protein complex tend to be chromosomally linked, likely resulting from natural selection for intracellular among-component dosage balance. These findings have implications for both the evolution of genome organization and optimal design of synthetic genomes in the face of gene expression noise. [ABSTRACT FROM AUTHOR]