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Summary: Carotenoids are indispensable to plants and critical components of the human diet. The carotenoid metabolic pathway is conserved across plant species, but our understanding of the genetic basis of carotenoid variation remains limited for the seeds of most cereal crops. To address this issue, we systematically performed linkage and association mapping for eight carotenoid traits using six recombinant inbred line (RIL) populations. Single linkage mapping (SLM) and joint linkage mapping (JLM) identified 77 unique additive QTLs and 104 pairs of epistatic QTLs. Among these QTLs, we identified 22 overlapping hotspots of additive and epistatic loci, highlighting the important contributions of some QTLs to carotenoid levels through additive or epistatic mechanisms. A genome‐wide association study based on all RILs detected 244 candidate genes significantly associated with carotenoid traits, 23 of which were annotated as carotenoid pathway genes. Effect comparisons suggested that a small number of loci linked to pathway genes have substantial effects on carotenoid variation in our tested populations, but many loci not associated with pathway genes also make important contributions to carotenoid variation. We identified ZmPTOX as the causal gene for a QTL hotspot (Q10/JLM10/GWAS019); this gene encodes a putative plastid terminal oxidase that produces plastoquinone‐9 used by two enzymes in the carotenoid pathway. Natural variants in the promoter and second exon of ZmPTOX were found to alter carotenoid levels. This comprehensive assessment of the genetic mechanisms underlying carotenoid variation establishes a foundation for rewiring carotenoid metabolism and accumulation for efficient carotenoid biofortification. [ABSTRACT FROM AUTHOR]

SUMMARY: Stalk lodging is a severe problem that limits maize production worldwide, although little attention has been given to its genetic basis. Here we measured rind penetrometer resistance (RPR), an effective index for stalk lodging, in a multi‐parent population of 1948 recombinant inbred lines (RILs) and an association population of 508 inbred lines (AMP508). Linkage and association mapping identified 53 and 29 single quantitative trait loci (QTLs) and 50 and 19 pairs of epistatic interactions for RPR in the multi‐parent population and AMP508 population, respectively. Phenotypic variation explained by all identified epistatic QTLs (up to ~5%) was much less than that explained by all single additive QTLs (up to ~33% in the multi‐parent population and ~ 60% in the AMP508 population). Among all detected QTLs, only eight single QTLs explained >10% of phenotypic variation in single RIL populations. Alleles that increased RPR were enriched in tropical/subtropical (TST) groups from the AMP508 population. Based on genome‐wide association studies in both populations, we identified 137 candidate genes affecting RPR, which were assigned to multiple biological processes, such as the biosynthesis of cell wall components. Sixty‐six candidate genes were cross‐validated by multiple methods or populations. Most importantly, 23 candidate genes were upregulated or downregulated in high‐RPR lines relative to low‐RPR lines, supporting the associations between candidate genes and RPR. These findings reveal the complex nature of the genetic basis underlying RPR and provide loci or candidate genes for developing elite varieties that are resistant to stalk lodging via molecular breeding. Significance Statement: Linkage and association mapping in multi‐parent and diverse natural populations revealed that a few large‐effect QTLs and many small‐effect QTLs contribute to the complex nature of maize stalk strength and provide loci or candidate genes for developing elite varieties with stalk lodging resistance via molecular breeding. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the deletion of an integral number of 3.3 kb units of the polymorphic D4Z4 repeat array at 4q35. The prenatal identification of this defect can be carried out on chorionic villi or amniocytes, whereas preimplantation genetic testing for monogenic disorders (PGT‐M) requires molecular markers linked to the D4Z4 allele of reduced size. In this context the reliability of this association is crucial. To test the informativeness of the nearby polymorphic markers we investigated recombination at 4q35 using the polymorphic markers D4S1523, D4S163 and D4S139 positioned at 0.55, 0.5 and 0.21 Mb proximal to the D4Z4 array respectively. We determined the probability of recombination events to occur in the D4Z4‐D4S1523 interval considering 86 subjects belonging to 12 FSHD families and found a recombination frequency of 14% between D4Z4 and D4S1523. Our study also revealed the occurrence of de novo variants and germline mosaicism. These findings highlight the recombinogenic nature of the 4q subtelomere and indicate that caution should be taken when interpreting PGT‐M results. It is advisable that a woman who underwent a PGT‐M cycle undertakes a prenatal DNA analysis to confirm the size of the D4Z4 alleles carried by the fetus. [ABSTRACT FROM AUTHOR]

Salt stress is a major limiting factor that severely affects the survival and growth of crops. It is important to understand the salt stress tolerance ability of Brassica napus and explore the underlying related genetic resources. We used a high‐throughput phenotyping platform to quantify 2111 image‐based traits (i‐traits) of a natural population under three different salt stress conditions and an intervarietal substitution line (ISL) population under nine different stress conditions to monitor and evaluate the salt stress tolerance of B. napus over time. We finally identified 928 high‐quality i‐traits associated with the salt stress tolerance of B. napus. Moreover, we mapped the salt stress‐related loci in the natural population via a genome‐wide association study and performed a linkage analysis associated with the ISL population, respectively. These results revealed 234 candidate genes associated with salt stress response, and two novel candidate genes, BnCKX5 and BnERF3, were experimentally verified to regulate the salt stress tolerance of B. napus. This study demonstrates the feasibility of using high‐throughput phenotyping‐based quantitative trait loci mapping to accurately and comprehensively quantify i‐traits associated with B. napus. The mapped loci could be used for genomics‐assisted breeding to genetically improve the salt stress tolerance of B. napus. [ABSTRACT FROM AUTHOR]

This study employs input‐output analysis to determine the extent of structural changes in the Indian economy, as well as how economic sector linkages changed between 2000 and 2019, and identifies the sectors with profound linkages with other sectors. Furthermore, we use the causative matrix to examine the temporal changes in intersectoral interactions. The analysis shows that manufacturing sectors have stronger intersectoral linkages than sevice sectors, with resource‐intensive and scale‐intensive manufacturing sectors having the most profound linkages. Furthermore, the causative matrix analysis reveals that Indian sectors became more externalized following the global financial crises, while receiving less feedback from other sectors. The results suggest that intersectoral linkages should be taken into account when designing industrial policies, and that investment should be encouraged in India's key economic sectors. [ABSTRACT FROM AUTHOR]

This study examines the key drivers of the information and communication technology (ICT) sector's growth and the dynamics of its sectoral relationships in the Chinese economy, about which little is known, by using four updated and harmonized input–output tables for the period 2002–2017. The decomposition analysis shows that the ICT sector's growth was mainly driven by the expansion of export and domestic demand in the 2002–2007 period and by domestic demand expansion in the 2007–2012 and 2012–2017 periods. Furthermore, causative matrix analysis demonstrates that the ICT sector was consistently externalized throughout the study period, regardless of whether it received limited feedback from non‐ICT sectors' final demand in the 2002–2007 and 2012–2017 periods or substantial feedback in the 2007–2012 period. Finally, linkage analysis reveals that the ICT sector has had profound intersectoral linkages with both supply‐ and demand‐side effects in the economy. We conclude that the ICT sector has been the engine of economic growth in China and that stimulating its growth is a key tool for economic development. [ABSTRACT FROM AUTHOR]

Synpolydactyly (SPD) is a digital malformation with the typical clinical phenotype of the webbing of 3/4 fingers and/or 4/5 toes, and combined with polydactyly. In this study, we investigated a Chinese family with SPD and genetic analysis found that all of the affected individuals in the family carry a heterozygous 11,451 bp microdeletion at chr2:176933872‐176945322 (GRCh37), which is located upstream of HOXD13 gene, the known disease gene for SPD1. All the affected individuals in the family carry the heterozygous deletion variant, and the variant co‐segregated with SPD in the family. Thus, we speculate that the 11,451 bp microdeletion is the disease‐causing variant in the family. To date, the microdeletion associating with SPD1 which we identified is the smallest deletion upstream of the HOXD13 gene and not altering the sequence of the HOXD13 gene. [ABSTRACT FROM AUTHOR]

Summary: Starch is the most abundant storage carbohydrate in maize kernels and provides calories for humans and other animals as well as raw materials for various industrial applications. Decoding the genetic basis of natural variation in kernel starch content is needed to manipulate starch quantity and quality via molecular breeding to meet future needs. Here, we identified 50 unique single quantitative trait loci (QTLs) for starch content with 18 novel QTLs via single linkage mapping, joint linkage mapping and a genome‐wide association study in a multi‐parent population containing six recombinant inbred line populations. Only five QTLs explained over 10% of phenotypic variation in single populations. In addition to a few large‐effect and many small‐effect additive QTLs, limited pairs of epistatic QTLs also contributed to the genetic basis of the variation in kernel starch content. A regional association study identified five non‐starch‐pathway genes that were the causal candidate genes underlying the identified QTLs for starch content. The pathway‐driven analysis identified ZmTPS9, which encodes a trehalose‐6‐phosphate synthase in the trehalose pathway, as the causal gene for the QTL qSTA4−2, which was detected by all three statistical analyses. Knockout of ZmTPS9 increased kernel starch content and, in turn, kernel weight in maize, suggesting potential applications for ZmTPS9 in maize starch and yield improvement. These findings extend our knowledge about the genetic basis of starch content in maize kernels and provide valuable information for maize genetic improvement of starch quantity and quality. [ABSTRACT FROM AUTHOR]

Summary: Lodging reduces grain yield in cereal crops. Understanding the genetic basis of lodging resistance (LR) benefits LR breeding. In the study, 524 accessions from a rice germplasm collection and 193 recombinant inbred lines were phenotyped for 17 LR‐related traits. Height and culm strength (the magnitude of applied force necessary to break the culm) were two major factors affecting LR. We conducted genome‐wide association study (GWAS) and identified 127 LR‐associated loci. Significant phenotypic correlations between culm‐strength traits and yield‐related traits were observed. To reveal the genetic relationship between them, we conducted GWAS of culm‐strength traits with adding yield‐related trait as a covariate and detected 63 loci linking culm strength and yield. As a proof, a near‐isogenic line for an association locus on chromosome 7 showed enhanced LR and yield. Strikingly, 58 additional loci were identified in the covariate‐added GWAS. Several LR‐associated loci had undergone divergent selection. Linkage analysis supported the GWAS results. We propose that introgression of alleles beneficial for both culm strength and panicle weight without negative effects on panicle number or pyramiding high‐yielding alleles and lodging‐resistant alleles without effects on yield can be employed for the post‐Green‐Revolution breeding. [ABSTRACT FROM AUTHOR]

Autosomal dominant hereditary polycystic kidney disease (ADPKD) is the most common inherited kidney disease that causes end‐stage renal disease and kidney failure. Preimplantation genetic testing for monogenic (PGT‐M) can effectively prevent the transmission of genetic diseases from parents to the offspring before pregnancy. However, PGT‐M currently adopts the single nucleotide polymorphism (SNP) linkage analysis for embryo's pathogenic gene carrying status and linkage analysis requires proband of the family. Here we report a new PGT‐M strategy using single sperm SNP linkage analysis for male patient with sporadic ADPKD caused by de novo PKD1 mutation. We recruited five couples with male patient with ADPKD caused by de novo PKD1 mutation, and 39 embryos from six PGT‐M cycles were detected. The five couples had at least one embryo that does not carry the PKD1 mutation. Within these five couples, the accuracy of carrier status of embryos was confirmed by amniotic fluid gene detection of two couples and two couples successfully delivered healthy fetuses. Therefore, the new PGT‐M strategy of using single sperm SNP linkage analysis was proved to be feasible and effective for male patient with ADPKD caused by de novo PKD1 mutation. [ABSTRACT FROM AUTHOR]

Autosomal‐recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood‐onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile‐onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next‐generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2‐related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N‐terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2‐related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well‐characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

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]

Summary: Hereditary thrombocytopenias can be subclassified based on mode of inheritance and platelet size. Here we report a family with autosomal dominant (AD) thrombocytopenia with normal platelet size. Linkage analysis and whole exome sequencing identified the R1026W substitution in ITGA2B as the causative defect. The same mutation has been previously reported in 7 Japanese families/patients with AD thrombocytopenia, but all of these patients had macrothrombocytopenia. This is the first report of a family with AD thrombocytopenia with normal platelet size resulting from mutation in ITGA2B. ITGA2B mutations should therefore be included in the differential diagnosis of this latter disorder. [ABSTRACT FROM AUTHOR]

Based on China's Input–Output Tables of 2002, 2007, and 2012, this paper employs a network analysis technique to evaluate the roles, positions, and evolution of tourism‐related sectors in industrial networks. The results revealed that China's tourism industrial network has loose density. The tourism‐related sectors have limited backward linkage effects and play limited intermediary roles in resource flows with regard to the rest of the economy, and the linkage strengths vary by sector. The sectors that occupy the same roles and positions as the tourism‐related sectors are concentrated in tertiary sectors. The service‐economy features of tourism‐related sectors are increasingly significant. [ABSTRACT FROM AUTHOR]

Purpose: To conduct a test of the principles underpinning crime linkage (behavioural consistency and distinctiveness) with a sample more closely reflecting the volume and nature of sexual crimes with which practitioners work, and to assess whether solved series are characterized by greater behavioural similarity than unsolved series. Method: A sample of 3,364 sexual crimes (including 668 series) was collated from five countries. For the first time, the sample included solved and unsolved but linked‐by‐DNA sexual offence series, as well as solved one‐off offences. All possible crime pairings in the data set were created, and the degree of similarity in crime scene behaviour shared by the crimes in each pair was quantified using Jaccard's coefficient. The ability to distinguish same‐offender and different‐offender pairs using similarity in crime scene behaviour was assessed using Receiver Operating Characteristic analysis. The relative amount of behavioural similarity and distinctiveness seen in solved and unsolved crime pairs was assessed. Results: An Area Under the Curve of.86 was found, which represents an excellent level of discrimination accuracy. This decreased to.85 when using a data set that contained one‐off offences, and both one‐off offences and unsolved crime series. Discrimination accuracy also decreased when using a sample composed solely of unsolved but linked‐by‐DNA series (AUC = .79). Conclusions: Crime linkage is practised by police forces globally, and its use in legal proceedings requires demonstration that its underlying principles are reliable. Support was found for its two underpinning principles with a more ecologically valid sample. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: Vascular adhesion protein‐1 (VAP‐1) is a membrane‐bound amine oxidase highly expressed in mature adipocytes and released into the circulation. VAP‐1 has been strongly implicated in several pathological processes, including diabetes, inflammation, hypertension, hepatic steatosis and renal diseases, and is an important disease marker and therapeutic target. Here, we aimed to identify the genetic loci for circulating VAP‐1 levels. Materials and Methods: We carried out a genomic‐wide linkage scan for the quantitative trait locus of circulating VAP‐1 levels in 1,100 Han Chinese individuals from 398 families in the Stanford Asian Pacific Program for Hypertension and Insulin Resistance study. Regional association fine mapping was carried out using additional single‐nucleotide polymorphisms. Results: The estimated heritability of circulating VAP‐1 levels is high (h2 = 69%). The most significant quantitative trait locus for circulating VAP‐1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds score of 4.11 (P = 6.86 × 10−6) in females. Regional single‐nucleotide polymorphism fine mapping within a 1‐unit support region showed the strongest association signals in the MACRO domain containing 2 (MACROD2) gene in females (P = 5.38 × 10−6). Knockdown of MACROD2 significantly suppressed VAP‐1 expression in human adipocytes, as well as the expression of key adipogenic genes. Furthermore, MACROD2 expression was found to be positively associated with VAP‐1 in human visceral adipose tissue. Conclusion: MACROD2 is a potential genetic determinant of serum VAP‐1 levels, probably through transcriptional regulation of adipogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Soybean mosaic virus (SMV) can cause serious yield losses in soybean. Soybean cultivar ‘RN‐9’ is resistant to 15 of 21 SMV strains. To well‐characterize this invaluable broad‐spectrum SMV‐resistance, populations (F1, F2 and F2:3) derived from resistant (R) × susceptible (S) and R × R crosses were tested for SMV‐SC18 resistance. Genetic analysis revealed that SC18 resistance in ‘RN‐9’ plus two elite SMV‐resistant genotypes (‘Qihuang No.1’ and ‘Kefeng No.1’) are controlled by independently single dominant genes. Linkage analysis showed that the resistance of ‘RN‐9’ to SMV strains SC10, SC14, SC15 and SC18 is controlled by more than one gene(s). Moreover, Rsc10‐r and Rsc18‐r were both positioned between the two simple sequence repeats markers Satt286 and Satt277, while Rsc14‐r was fine‐mapped in 136.8‐kb genomic region containing sixteen genes, flanked by BARCSOYSSR_06_0786 and BARCSOYSSR_06_0790 at genetic distances of 3.79 and 4.14 cM, respectively. Allelic sequence comparison showed that Cytochrome P450‐encoding genes (Glyma.06g176000 and Glyma.06g176100) likely confer the resistance to SC14 in ‘RN‐9’. Our results would facilitate the breeding of broad‐spectrum and durable SMV resistance in soybeans. [ABSTRACT FROM AUTHOR]

Summary: The clinical genetics of genetic generalized epilepsy suggests complex inheritance; large pedigrees, with multiple affected individuals, are rare exceptions. We studied a large consanguineous family from Turkey where extensive electroclinical phenotyping revealed a familial phenotype most closely resembling juvenile myoclonic epilepsy. For a subject to be considered affected (n = 14), a diagnostic electroencephalogram was required. Seizure onset ranged between 6 and 19 years (mean = 12 years). Thirteen of 14 experienced myoclonic jerks; in 11, this was associated with eyelid blinking, and in 10 it was interspersed with absences. Generalized tonic–clonic seizures were seen in 11. One individual had generalized tonic–clonic seizures alone. Electroencephalograms demonstrated generalized polyspike and wave discharges that were not associated with photoparoxysmal response. Intellect was normal. Nineteen family members were subsequently chosen for nonparametric multipoint linkage analyses, which identified a 39.5 Mb region on chromosome 5 (P < 0.0001). Iterative analysis, including discovery of a subtly affected individual, narrowed the critical region to 15.4 Mb and possibly to 5.5 Mb. Homozygous versus heterozygous state of the refined 5p13.2‐q11.1 haplotype was not associated with phenotypic severity or onset age, suggesting that one versus two pathogenic variants may result in similar phenotypes. Whole exome sequencing (n = 3) failed to detect any rare, protein‐coding variants within the highly significant linkage region that includes HCN1 as a promising candidate. [ABSTRACT FROM AUTHOR]

The identification of novel genetic modifiers of age‐at‐onset (AAO) of Alzheimer's disease (AD) could advance our understanding of AD and provide novel therapeutic targets. A previous genome scan for modifiers of AAO among families affected by early‐onset AD caused by the PSEN2 N141I variant identified 2 loci with significant evidence for linkage: 1q23.3 and 17p13.2. Here, we describe the fine‐mapping of these 2 linkage regions, and test for replication in 6 independent datasets. By fine‐mapping these linkage signals in a single large family, we reduced the linkage regions to 11% their original size and nominated 54 candidate variants. Among the 11 variants associated with AAO of AD in a larger sample of Germans from Russia, the strongest evidence implicated promoter variants influencing NCSTN on 1q23.3 and ZBTB4 on 17p13.2. The association between ZBTB4 and AAO of AD was replicated by multiple variants in independent, trans‐ethnic datasets. Our results show association between AAO of AD and both ZBTB4 and NCSTN. ZBTB4 is a transcriptional repressor that regulates the cell cycle, including the apoptotic response to amyloid beta, while NCSTN is part of the gamma secretase complex, known to influence amyloid beta production. These genes therefore suggest important roles for amyloid beta and cell cycle pathways in AAO of AD. [ABSTRACT FROM AUTHOR]

Summary: Objective: Juvenile myoclonic epilepsy (JME) is a common adolescent‐onset genetic generalized epilepsy (GGE) syndrome. Multiple linkage and association studies have found that BRD2 influences the expression of JME. The BRD2‐JME connection is further corroborated by our murine model; Brd2 haploinsufficiency produces characteristics that typify the clinical hallmarks of JME. Neither we, nor several large‐scale studies of JME, found JME‐related BRD2 coding mutations. Therefore, we investigated noncoding BRD2 regions, seeking the origin of BRD2's JME influence. BRD2's promoter harbors a JME‐associated single nucleotide polymorphism (rs3918149) and a CpG (C‐phosphate‐G dinucleotides) island (CpG76), making it a potential “hotspot” for JME‐associated epigenetic variants. Methylating promoter CpG sites causes gene silencing, often resulting in reduced gene expression. We tested for differences in DNA methylation at CpG76 in 3 different subgroups: (1) JME patients versus their unaffected family members, (2) JME versus patients with other forms of GGE, and (3) Caucasian versus non‐Caucasian JME patients. Methods: We used DNA pyrosequencing to analyze the methylation status of 10 BRD2 promoter CpG sites in lymphoblastoid cells from JME patients of Caucasian and non‐Caucasian origin, unaffected family members, and also non‐JME GGE patients. We also measured global methylation levels and DNA methyl transferase 1 (DNMT1) transcript expression in JME families by standard methods. Results: CpG76 is highly methylated in JME patients compared to unaffected family members. In families with non‐JME GGE, we found no relationship between promoter methylation and epilepsy. In non‐Caucasian JME families, promoter methylation was mostly not associated with epilepsy. This makes the BRD2 promoter a JME‐specific, ethnicity‐specific, differentially methylated region. Global methylation was constant across groups. Significance: BRD2 promoter methylation in JME, and the lack of methylation in unaffected relatives, in non‐JME GGE patients, and in non‐Caucasian JME, demonstrate that methylation specificity is a possible seizure susceptibility motif in JME risk and suggests JME therapeutics targeting BRD2. [ABSTRACT FROM AUTHOR]

Here we review the current understanding of the genetic architecture of intracranial berry aneurysms (IBA) to aid in the genetic counseling of patients at risk for this condition. The familial subtype of IBA, familial intracranial aneurysms (FIA), is associated with increased frequency of IBA, increased risk of rupture, and increased morbidity and mortality after rupture. Family history is the strongest predictor for the development of IBA. However, a genetic test is not yet available to assess risk within a family. Studies using linkage analysis, genome-wide association, and next-generation sequencing have found several candidate loci and genes associated with disease onset, but have not conclusively implicated a single gene. In addition to family history, a separate or concurrent diagnosis of autosomal dominant polycystic kidney disease is a strong genetic risk factor for IBA formation. We also discuss the relative risk for developing IBA in several Mendelian syndromes including vascular Ehlers-Danlos syndrome, Marfan syndrome, Neurofibromatosis Type I, and Loeys-Dietz syndrome. [ABSTRACT FROM AUTHOR]

Background: Essential tremor is a neurological condition characterized by tremor during voluntary movement. To date, 3 loci linked to familial essential tremor have been identified.Methods: We examined 48 essential tremor patients in 5 large essential tremor pedigrees in our data set for genetic linkage using an Affymetrix Axiom array. Linkage analysis was performed using an affecteds-only dominant model in SIMWALK2. To incorporate all genotype information, GERMLINE was used to identify genome segments shared identical-by-descent in pairs of affecteds. Exome sequencing was performed in pedigrees showing evidence of linkage.Results: For one family, chromosomes 5 and 18 showed genome-wide significant linkage to essential tremor. Shared segment analysis excluded the 18p11 candidate region and reduced the 5q35 region by 1 megabase. Exome sequencing did not identify a potential causative variant in this region.Conclusion: A locus on chromosome 5 is linked to essential tremor. Further research is needed to identify a causative variant. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Developmental dysplasia of the hip ( DDH) is one of the most common skeletal anomalies. DDH encompasses a spectrum of the disorder ranging from minor acetabular dysplasia to irreducible dislocation, which may lead to premature arthritis in later life. Involvement of genetic factors underlying DDH became evident when several studies reported chromosomal loci linked to DDH in families with multiple affected individuals. Moreover, using association studies, variants in genes involved in chondrogenesis and joint formation have been shown to be associated with DDH. At least, one study identified a pathogenic variant in the chemokine receptor gene in DDH. No genetic analysis has been reported or carried out in DDH patients from the Middle East. Here, we review the literature related to genetics of DDH and emphasized the usefulness of new generation technologies in identifying genetic variants underlying DDH in consanguineous families. [ABSTRACT FROM AUTHOR]

Flowering time is one of the major adaptive traits in domestication of maize and an important selection criterion in breeding. To detect more maize flowering time variants we evaluated flowering time traits using an extremely large multi- genetic background population that contained more than 8000 lines under multiple Sino-United States environments. The population included two nested association mapping ( NAM) panels and a natural association panel. Nearly 1 million single-nucleotide polymorphisms ( SNPs) were used in the analyses. Through the parallel linkage analysis of the two NAM panels, both common and unique flowering time regions were detected. Genome wide, a total of 90 flowering time regions were identified. One-third of these regions were connected to traits associated with the environmental sensitivity of maize flowering time. The genome-wide association study of the three panels identified nearly 1000 flowering time-associated SNPs, mainly distributed around 220 candidate genes (within a distance of 1 Mb). Interestingly, two types of regions were significantly enriched for these associated SNPs - one was the candidate gene regions and the other was the approximately 5 kb regions away from the candidate genes. Moreover, the associated SNPs exhibited high accuracy for predicting flowering time. [ABSTRACT FROM AUTHOR]

Optimum flowering time is the key to maximize canola production in order to meet global demand of vegetable oil, biodiesel and canola-meal. We reveal extensive variation in flowering time across diverse genotypes of canola under field, glasshouse and controlled environmental conditions. We conduct a genome-wide association study and identify 69 single nucleotide polymorphism (SNP) markers associated with flowering time, which are repeatedly detected across experiments. Several associated SNPs occur in clusters across the canola genome; seven of them were detected within 20 Kb regions of a priori candidate genes; FLOWERING LOCUS T, FRUITFUL, FLOWERING LOCUS C, CONSTANS, FRIGIDA, PHYTOCHROME B and an additional five SNPs were localized within 14 Kb of a previously identified quantitative trait loci for flowering time. Expression analyses showed that among FLC paralogs, BnFLC.A2 accounts for ~23% of natural variation in diverse accessions. Genome-wide association analysis for FLC expression levels mapped not only BnFLC.C2 but also other loci that contribute to variation in FLC expression. In addition to revealing the complex genetic architecture of flowering time variation, we demonstrate that the identified SNPs can be modelled to predict flowering time in diverse canola germplasm accurately and hence are suitable for genomic selection of adaptative traits in canola improvement programmes. [ABSTRACT FROM AUTHOR]

Brachiariagrass is an important tropical forage grass cultivated around the world. Despite its global importance, the development of brachiariagrass breeding programs was delayed by the complications of recombining aposporous apomictic genotypes until the late 1980s. 'Mulato' is the first apomictic hybrid cultivar of brachiariagrass with the development of synthetic sexual tetraploid lines. An amplified fragment-length polymorphism ( AFLP) linkage map of the apomictic pollen donor 'Mulato' was developed to identify molecular markers for apospory. The map contained 29 linkage groups with 272 markers. Twelve tightly clustered AFLP markers related to apospory were identified in linkage group 2. Furthermore, we identified quantitative trait loci ( QTLs) for leaf width, leaf shape ratio (width/length), stem diameter and percentage of filled seeds using simple interval mapping and composite interval mapping. The AFLP markers tightly linked to apospory and QTLs associated with important agronomical traits will be valuable tools for marker-assisted selection in brachiariagrass improvement programs. [ABSTRACT FROM AUTHOR]

Introduction We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. Methods We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. Results We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLOD max = 4.7, P joint = 6.6 × 10 −6 ), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLOD max = 4.9, P joint = 1.2 × 10 −5 ), a region harboring genes associated with the nervous system ( GARS , GHRHR, and NEUROD6 ). Discussion Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations. [ABSTRACT FROM AUTHOR]

Linkage analysis has, albeit occasionally, been presented in courts across the world as evidence that a series of offences possess behavioural similarities and distinctiveness from other offences, meaning they have probably been committed by the same individual. It is therefore imperative to ascertain how linkage analysis is regarded by juries within the context of deliberations. Three groups of participants (N = 22) eligible for jury duty in England and Wales viewed a simulated rape and murder trial derived from an actual South African case. Linkage analysis formed the sole evidence against the defendant in the two later offences, although DNA matches and eyewitness identifications of the defendant were present in the two earlier offences. Participant deliberations were recorded and subjected to thematic analysis. Five themes were discovered: behavioural consistencies and inconsistencies, physical versus case linkage evidence, barriers to admissibility, potential uses of linkage analysis, and dependence of lay knowledge. Jurors' over-reliance on erroneous lay knowledge contributed to their conclusion that linkage analysis is, at present, unrepresentative evidence that cannot independently indicate a defendant's culpability. However, participants believed that linkage analysis could be a useful tool within investigations and, with further research evidence, in court in England and Wales. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Soybean mosaic virus (SMV) disease is one of the most serious and broadly distributed soybean ( Glycine max (L.) Merr.) diseases. Here, we combine the advantages of association and linkage analysis to identify and fine-map the soybean genes associated with resistance to SMV strain SC7. A set of 191 soybean accessions from different geographic origins and 184 recombinant inbred lines (RILs) derived from Kefeng No.1 (resistant) × Nannong 1138-2 (susceptible) were used in this study. The SC7 resistance genes were previously mapped to a 2.65 Mb region on chromosome 2 and a 380 kb region on chromosome 13. Among 19 single nucleotide polymorphisms (SNPs) detected via association analysis in the study, the SNP BARC-021625-04157 was located in the 2.65 Mb region, and the SNP BARC-041671-08065 was located near the 380 kb region; three genes harboring the SNPs were probably related to SC7 resistance. The resistance gene associated with BARC-021625-04157 was then fine-mapped to a region of approximately 158 kb on chromosome 2 using 184 RILs. Among the 15 genes within this region, one NBS-LRR type gene, one HSP40 gene and one serine carboxypeptidase-type gene might be candidate SC7 resistance genes. These results will be useful for map-based cloning and marker-assisted selection in soybean breeding programs. [ABSTRACT FROM AUTHOR]

In this study, we describe the development and characterization of the first high-density single nucleotide polymorphism ( SNP) genotyping array for rainbow trout. The SNP array is publically available from a commercial vendor (Affymetrix). The SNP genotyping quality was high, and validation rate was close to 90%. This is comparable to other farm animals and is much higher than previous smaller scale SNP validation studies in rainbow trout. High quality and integrity of the genotypes are evident from sample reproducibility and from nearly 100% agreement in genotyping results from other methods. The array is very useful for rainbow trout aquaculture populations with more than 40 900 polymorphic markers per population. For wild populations that were confounded by a smaller sample size, the number of polymorphic markers was between 10 577 and 24 330. Comparison between genotypes from individual populations suggests good potential for identifying candidate markers for populations' traceability. Linkage analysis and mapping of the SNPs to the reference genome assembly provide strong evidence for a wide distribution throughout the genome with good representation in all 29 chromosomes. A total of 68% of the genome scaffolds and contigs were anchored through linkage analysis using the SNP array genotypes, including ~20% of the genome assembly that has not been previously anchored to chromosomes. [ABSTRACT FROM AUTHOR]

Eye misalignment, called strabismus, is amongst the most common phenotypes observed, occurring in up to 5% of individuals in a studied population. While misalignment is frequently observed in rare complex syndromes, the majority of strabismus cases are non-syndromic. Over the past decade, genes and pathways associated with syndromic forms of strabismus have emerged, but the genes contributing to non-syndromic strabismus remain elusive. Genetic testing for strabismus risk may allow for earlier diagnosis and treatment, as well as decreased frequency of surgery. We review human and model organism literature describing non-syndromic strabismus, including family, twin, linkage, and gene expression studies. Recent advances in the genetics of Duane retraction syndrome are considered, as relatives of those impacted show elevated familial rates of non-syndromic strabismus. As whole genome sequencing efforts are advancing for the discovery of the elusive strabismus genes, this overview is intended to support the interpretation of the new findings. [ABSTRACT FROM AUTHOR]

Objective To clinically and genetically characterize a large Brazilian family with autosomal dominant partial epilepsy with auditory features ( ADPEAF) not related to leucine-rich, glioma-inactivated 1 ( LGI1) gene. Methods Seventy family members (four married-ins) participating in the study were assessed by a detailed clinical interview and a complete neurologic examination. Genetic mapping was conducted through autosome-wide single nucleotide polymorphism ( SNP) genotyping and subsequent linkage analysis on 16 and haplotype analysis on 25 subjects, respectively. Results The pedigree comprised 15 affected members, of whom 11 were included in the study ( male/ female: 6/5; mean age 39.5 years). All but two ( III:22 and IV:92) had focal seizures with auditory aura followed by secondary generalization in 44.4%. The mean age at onset of epilepsy seizures was 13.7 years. Initial autosome-wide SNP linkage analysis conducted on 12 subjects (8 affected) pointed to a single genomic region on chromosome 19 with a maximum multipoint logarithm of the odds ( LOD) score of 2.60. Further refinement of this region through SNP and microsatellite genotyping on 16 subjects (11 affected) increased the LOD score to 3.41, thereby establishing 19q13.11-q13.31 as a novel ADPEAF locus. Haplotype analysis indicated that the underlying mutation is most likely located in a 9.74 Mb interval between markers D19 S416 and D19 S420. Sequence analysis of the most prominent candidate genes within this critical interval ( SCN1B , LGI4 , KCNK6 , and LRFN1) did not reveal any mutation. Significance This study disclosed a novel ADPEAF locus on chromosome 19q13.11-q13.31, contributing to future identification of a second dominant gene for this epileptic syndrome. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Anterior segment dysgenesis refers to a spectrum of disorders affecting structures in the anterior segment of the eye including the iris, cornea and trabecular meshwork. Approximately 50% of patients with anterior segment dysgenesis develop glaucoma. Traditional genetic methods using linkage analysis and family-based studies have identified numerous disease-causing genes such as PAX6, FOXC1 and PITX2. Despite these advances, phenotypic and genotypic heterogeneity pose continuing challenges to understand the mechanisms underlying the complexity of anterior segment dysgenesis disorders. Genomic methods, such as genome-wide association studies, are potentially an effective tool to understand anterior segment dysgenesis and the individual susceptibility to the development of glaucoma. In this review, we provide the rationale, as well as the challenges, to utilizing genomic methods to examine anterior segment dysgenesis disorders. [ABSTRACT FROM AUTHOR]

Background and purpose Mutations in the SACS gene are commonly associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay ( ARSACS), a complex neurodegenerative disorder characterized by progressive degeneration of the cerebellum and spinal cord tracts. The aim of this study was to identify the genetic cause of the disease in an Italian family with spastic paraplegia and peripheral neuropathy. Methods Affected subjects were subjected to a comprehensive neurological examination including electromyography and brain magnetic resonance imaging. Genetic studies included exclusion of known disease genes, genome-wide linkage analysis using high density single nucleotide polymorphism genotyping and candidate gene sequencing. Results Molecular analyses revealed a novel missense mutation in the SACS gene (c.11,104A>G) occurring in a homozygous state in patients and absent in 700 Italian control chromosomes. The mutation led to the amino acid substitution p.Thr3702Ala in the sacsin protein, in a possible protein−protein interaction site of UBE3A binding domain. Conclusion This study broadens the genetic spectrum of SACS mutations and expands the clinical ARSACS phenotype suggesting that the SACS gene can be considered in patients with non-canonical ARSACS clinical presentations. [ABSTRACT FROM AUTHOR]

We describe a family that segregated an autosomal dominant form of craniosynostosis characterized by variable expression and limited extra-cranial features. Linkage analysis and genome sequencing were performed to identify the underlying genetic mutation. A c.443C>T missense mutation in MSX2, which predicts p.Pro148Leu was identified and segregated with the disease in all affected family members. One other family with autosomal dominant craniosynostosis (Boston type) has been reported to have a missense mutation in MSX2. These data confirm that missense mutations altering the proline at codon 148 of MSX2 cause dominantly inherited craniosynostosis. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background and Aims Gallstone disease ( GD) is a common disease of multigenetic origin; however, the major susceptibility loci for GD in human populations remain unidentified. This study aimed to identify the genetic factors contributing to gallstone development in Chinese. Methods A genome-wide scan was conducted in 12 Han Chinese GD families to identify linkage loci. The linkage region showing the highest logarithm of odds score encompasses the sterol 12α-hydroxylase gene ( CYP8 B1). Replication analysis with an independent sample of 192 GD patients and 192 unrelated, matched controls was carried out to verify the associations between CYP8 B1 polymorphisms and GD. Results Three loci ( D3 S1266, D4 S406, and D9 S1682) showed suggestive or nominal evidence of linkage in all 12 GD families. The logarithm of odds score of D3 S1266 reached 2.71 in the families with late-onset patients. The single nucleotide polymorphism rs3732860 in the 3′-untranslated region of CYP8 B1 showed significant association to GD ( P = 0.022), and carriers of the A allele had lower risk of GD (odds ratio = 1.46, 95% confidence interval: 1.055-2.034) compared with carriers of the G allele. Conclusions The single nucleotide polymorphism rs3732860 in the 3′-untranslated region of the CYP8 B1 gene is associated with risk of GD in Chinese Han and appears to be responsible for the observed linkage with D3 S1266. [ABSTRACT FROM AUTHOR]

Analysis of genetic linkage to dyslexia was performed using 133,165 array-based SNPs genotyped in 718 persons from 101 dyslexia-affected families. Results showed five linkage peaks with lod scores >2.3 (4q13.1, 7q36.1-q36.2, 7q36.3, 16p12.1, and 17q22). Of these five regions, three have been previously implicated in dyslexia (4q13.1, 16p12.1, and 17q22), three have been implicated in attention-deficit hyperactivity disorder ( ADHD, which highly co-occurs with dyslexia; 4q13.1, 7q36.3, 16p12.1) and four have been implicated in autism (a condition characterized by language deficits; 7q36.1-q36.2, 7q36.3, 16p12.1, and 17q22). These results highlight the reproducibility of dyslexia linkage signals, even without formally significant lod scores, and suggest dyslexia predisposing genes with relatively major effects and locus heterogeneity. The largest lod score (2.80) occurred at 17q22 within the MSI2 gene, involved in neuronal stem cell lineage proliferation. Interestingly, the 4q13.1 linkage peak (lod 2.34) occurred immediately upstream of the LPHN3 gene, recently reported both linked and associated with ADHD. Separate analyses of larger pedigrees revealed lods >2.3 at 1-3 regions per family; one family showed strong linkage (lod 2.9) to a known dyslexia locus (18p11) not detected in our overall data, demonstrating the value of analyzing single large pedigrees. Association analysis identified no SNPs with genome-wide significance, although a borderline significant SNP ( P = 6 × 10-7) occurred at 5q35.1 near FGF18, involved in laminar positioning of cortical neurons during development. We conclude that dyslexia genes with relatively major effects exist, are detectable by linkage analysis despite genetic heterogeneity, and show substantial overlapping predisposition with ADHD and autism. [ABSTRACT FROM AUTHOR]

When relying on crime scene behaviours to link serial crimes, linking accuracy may be influenced by the measure used to assess across-crime similarity and the types of behaviours included in the analysis. To examine these issues, the present study compared the level of linking accuracy achieved by using the simple matching index (S) to that of the commonly used Jaccard's coefficient (J) across themes of arson behaviour. The data consisted of 42 crime scene behaviours, separated into three behavioural themes, which were exhibited by 37 offenders across 114 solved arsons. The results of logistic regression and receiver operating characteristic analysis indicate that, with the exception of one theme where S was more effective than J at discriminating between linked and unlinked crimes, no significant differences emerged between the two similarity measures. In addition, our results suggest that thematically unrelated behaviours can be used to link crimes with the same degree of accuracy as thematically related behaviours, potentially calling into the question the importance of theme-based approaches to behavioural linkage analysis. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The present study examines consistency of crime behaviour among 347 sexual assaults committed by 69 serial sex offenders. This individual behaviour approach-the so-called signature approach-reveals which features of crime behaviour are consistent across a series and which features are not. The consistency scores were calculated using the Jaccard's coefficient. The results of this study indicate that there are some crime features of a serial sexual assault that can be useful for the purpose of linkage. Another important finding is that consistency scores for different variables within the same category can differ substantially. Moreover, serial sex offenders are more likely to be consistent in their environmental crime features when they are also consistent in their behavioural features, and vice versa. Serial sex offenders are also more likely to be consistent in the behavioural features of their assaults as the crime series gets longer. The implications of the results are discussed in relation to both research and practise. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the case linkage principles, behavioural consistency and distinctiveness, with a sample of serial car thieves. Target selection, acquisition, and disposal behaviours, as well as geographical and temporal behaviours, were examined. The effects of temporal proximity and offender expertise were also investigated as moderating factors of behavioural consistency. As in previous case linkage research, geographical and some target selection behaviours were able to predict whether crime pairs are linked or unlinked at a statistically significant level. Crucially, it was also found that temporal behaviours demonstrate a significant capability to predict linkage status, a variable which has never before been applied to the prediction of linkage in serial car theft. Furthermore, it was demonstrated that changing the operationalisation of the behavioural domains can affect the results obtained. No support was found for the moderation of behavioural consistency on the basis of temporal proximity or expertise. Overall, the results support previous case linkage studies, furthering their practical applicability within the criminal justice system. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A previous genome scan that was conducted in Spanish Churra sheep identified a significant quantitative trait locus (QTL) for milk protein percentage (PP) on chromosome 3 (OAR3), between markers KD103 and OARVH34. The aim of this study was to replicate these results and to refine the mapped position of this QTL. To accomplish this goal, we analysed 14 new half-sib families of Spanish Churra sheep including 1661 ewes from 29 different flocks. These animals were genotyped for 21 microsatellite markers mapping to OAR3. In addition to a classical linkage analysis (LA), a combined linkage disequilibrium and linkage analysis (LDLA) was performed with the aim of enhancing the resolution of the QTL mapping. The LA that was performed in this sheep population identified the presence of a highly significant QTL for PP near marker KD103 ( Pc < 0.001; Pexp < 0.001). The phenotypic variance that was owing to the QTL was 2.74%. Two segregating families for the target QTL were identified in this population with QTL effect estimates of 0.47 and 0.95 SD. The LDLA identified the same QTL as the previous analyses with a high level of statistical significance ( P = 9.184 E-11) and narrowed the confidence interval (CI) to a 13 cM region. These results confirm the segregation of the previously identified OAR3 QTL that influences PP in Spanish Churra sheep. Future research will aim to increase the marker density across the refined CI and to analyse the corresponding candidate genes to identify the allelic variant or variants that underlie this genetic effect. [ABSTRACT FROM AUTHOR]

Despite enormous data collection and analysis efforts, the genetic influences on common epilepsies remain mostly unknown. We propose that reasons for the lack of progress can be traced to three factors: (1) A reluctance to consider fine-grained phenotype definitions based on extensive and carefully collected clinical data; (2) the pursuit of genetic analysis methods that are popular but poorly conceived and are inadequate to the task of resolving the problems inherent in common disease studies; (3) preconceived ideas about the genetic mechanisms that cause epilepsy (which we have discussed elsewhere). We propose a paradigm for finding epilepsy-related loci and alleles that has proven successful in other common diseases. [ABSTRACT FROM AUTHOR]

. Haemophilia A (HA) is the most common hereditary bleeding disorder caused by F8 gene mutation. Linkage analysis is an auxiliary strategy to direct mutation analysis for genetic counselling of HA. Here we characterize and validate a novel panel of six short tandem repeat (STR) loci for genetic counselling in Chinese HA pedigrees. The panel was analysed in 116 unrelated healthy female patients and 108 male patients, and verified in 169 unrelated pedigrees with HA. The six STR loci in the panel spanned a distance of 0.3 Mb from each side of the F8 gene. Three of them, F8Up226, F8Up146 and F8Down48, were first described here. Markers F8Up226, F8Up146, F8Int13, F8Int25, F8Down48 and DXS1073 exhibited the number of alleles 16, 9, 8, 6, 9 and 10, and heterozygosity rates of 74.8%, 44.8%, 60.9%, 42.6%, 61.7% and 62.0% respectively. Haplotype frequencies analysis suggested that the genotypes of haplotype provided a highly informative content (56.5%). The panel was informative in 167 of 169 unrelated haemophilic pedigrees with the combined diagnostic rate of 98.8%. In eight pedigrees could not be diagnosed by mutation detection linkage studies using the panel were informative in all the pedigrees and a reliable diagnosis was made in seven pedigrees. The novel panel of the six STR loci represents a high degree of informativeness and a low fraction of recombination. Linkage analysis using this panel provides an alternative strategy when direct mutation detection is not feasible for genetic counselling in Chinese HA families. [ABSTRACT FROM AUTHOR]

Al-Owain M, Wakil S, Shareef F, Al-Fatani A, Hamadah E, Haider M, Al-Hindi H, Awaji A, Khalifa O, Baz B, Ramadhan R, Meyer B. Novel homozygous mutation in DSP causing skin fragility-woolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes. Desmoplakin is an important cytoskeletal linker for the function of the desmosomes. Linking desmoplakin to certain types of cardiocutaneous syndromes has been a hot topic recently. Skin fragility-woolly hair syndrome is a rare autosomal recessive disorder involving the desmosomes and is caused by mutation in the desmoplakin gene ( DSP). We report five members from a large family with skin fragility-woolly hair syndrome. The index is a 14-year-old girl with palmoplantar keratoderma, woolly hair, variable alopecia, dystrophic nails, and excessive blistering to trivial mechanical trauma. No cardiac symptoms were reported. Although formal cardiac examination was not feasible, the echocardiographic evaluation of the other two affected younger siblings was normal. Homozygosity mapping and linkage analysis revealed a high LOD score region in the short arm of chromosome 6 that harbors the DSP. Full sequencing of the DSP showed a novel homozygous c.7097 G >A (p.R2366H) mutation in all affected members, and the parents were heterozygous. This is the report of the third case/family of the skin fragility-woolly hair syndrome in the literature. We also present a clinical and molecular review of various desmoplakin-related phenotypes, with emphasis on onset of cardiomyopathy. The complexity of the desmoplakin and its variable presentations warrant introducing the term 'desmoplakinopathies' to describe all the phenotypes related to defects in the desmoplakin. [ABSTRACT FROM AUTHOR]

Generalized epilepsies are clinically and genetically heterogeneous syndromes. Idiopathic generalized epilepsy (IGE), which has a strong genetic background, is not associated with any additional clinical features, such as mental retardation (MR). Herein we report results of linkage analysis in a large family with autosomal dominant (AD) generalized epilepsy associated with MR. We identified a four-generation kindred with several affected members with generalized epilepsy without any evidence for secondary causes. Electroencephalography (EEG) studies and magnetic resonance imaging (MRI) results were reviewed when available. We performed a genome-wide linkage analysis. Fourteen individuals were classified as affected and an additional three were considered as nonpenetrant obligatory carriers. Thirteen affected individual had a history of generalized tonic-clonic seizures, and absence seizures were reported in nine affected individuals. There was no history of preceding febrile seizures. MR was present in nine affected individuals with epilepsy but the other affected individuals had normal intelligence. Neuroimaging did not reveal any structural abnormalities and EEG studies were consistent with IGE rather than symptomatic generalized epilepsy. Genetic analysis detected a group of markers with logarithmic (base 10) of odds (LOD) score >3 on chromosome 3p spanning a 5.5 Mbp region. Sequencing of several candidate genes, including dynein light chain-A, golgin subfamily a4, leucine rich repeat (in FLII) interacting gene, s erine/threonine-protein kinase DCAMKL3 (doublecortin- like and CAM kinase-like 3), laforin (EPM2A) interacting protein 1 (EPM2AIP1, programmed cell death 6 interacting protein, and CLIP-associating protein 2 (cytoplasmic linker-associated protein 2) (hOrbit2) genes did not identify the disease-causing mutations. We report the identification of a genetic locus for generalized epilepsy associated with MR on chromosome 3p. Affected individuals have a form of genetic epilepsy with generalized seizures variably associated with MR Despite the presence of MR in several affected patients, epilepsy phenotype was not fully consistent with symptomatic epilepsy and suggests a biologic continuum between symptomatic epilepsies and IGE. [ABSTRACT FROM AUTHOR]