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Pedigrees
Kinds of Pedigrees Terms modified by Pedigrees Selected AbstractsAutosomal Dominant Early-onset Cortical Myoclonus, Photic-induced Myoclonus, and Epilepsy in a Large PedigreeEPILEPSIA, Issue 10 2006Elena Gardella Summary:,Purpose: Cortical tremor, a form of rhythmic cortical myoclonus (rhythmic CM), and epilepsy have been described in families with autosomal dominant inheritance. Linkage analyses revealed two putative loci on chromosome 2p and 8q. Clinical photosensitivity was not a prominent feature in such families. We describe a large Italian family with rhythmic CM, photosensitivity, and epilepsy. Methods: Twenty-three individuals of a five-generation family were studied. Linkage analyses for the loci on chromosome 2p11.1 and 8q23.3 were performed. Results: Of the 23 studied family members, 16 were affected. Rhythmic CM of childhood onset was present in all 16 individuals (onset ranging from 3 to 12 years), was associated with photic-induced myoclonic jerks in seven, and with epileptic seizures in six (onset ranging from 23 to 34 years). Five children of the V generation manifested also episodes of arousal with generalized tremor in early infancy ("tremulous arousals"). Jerk-locked back-averaging of rhythmic CM of six affected individuals, documented a premyoclonic EEG correlate. C-reflex at rest was present in two affected adults. Linkage analyses excluded mapping to the 2p11.1 and 8q23.3 loci. Conclusions: Clinical variability and severity of the phenotypes in this family are in line with those of previously described pedigrees with autosomal dominant cortical myoclonus and epilepsy. In this family, a progression of symptoms was found: rhythmic CM and tremulous arousals occurred in childhood, whereas visually induced manifestations and epileptic seizures occurred during adolescence,adulthood. Exclusion of linkage to the two known loci is consistent with genetic heterogeneity of such familial clustering of symptoms. [source] Using pedigree information to monitor genetic variability of endangered populations: the Xalda sheep breed of Asturias as an exampleJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 2 2003F. Goyache Summary The aim of this work is to highlight the need of monitoring small populations to conserve their genetic variability by using a set of parameters to characterize both the structure of populations and management practices. As a representative example we analyse the pedigree information of the endangered Xalda sheep breed of Asturias. The herdbook of Xalda sheep included a total of 805 animals and 62 herds. The number of founders was 329. Nowadays, there are 562 live animals and 26 active herds. The breed is in risk of losing genetic diversity because of the abusive use of certain individuals as parents. The effective number of founder animals is 81.1. The effective number of founder herds is 9.9. The average value of inbreeding in the whole Xalda population was 1.5%. The average relatedness (AR) coefficient reached 1.8% in the whole pedigree. The genetic representation of the lines of founders is unbalanced. Inbreeding trends and effective size do not provide realistic information concerning the risk of loss of diversity as a result of the shallowness of the genealogical information. We suggest the monitoring of the breed using AR to unbalance the genetic contributions of specific individuals, equalizing the genetic representation of the founders and lines in the population. In addition, AR can suggest the introduction of new, under-represented animals in herds showing high average AR values relative to the population. Our results can be useful to improve the development of conservation initiatives involving open herdbooks to avoid the risk of loss of genetic diversity caused by incorrect management practices. Zusammenfassung Verwendung von Pedigree Informationen zur Konservierung genetischer Variabilität in gefährdeten Populationen: Das asturische Xalda Schaf als Beispiel Das Ziel dieser Arbeit ist es, die Notwendigkeit hervorzuheben, Pedigree Informationen in kleinen Populationen durch Verwendung bestimmter Parameter zu analysieren, um sowohl die Struktur der Populationen als auch Managementmaßnahmen zu charakterisieren. Als repräsentatives Beispiel analysieren wir Pedigree Informationen des gefährdeten Xalda Schafes in Asturien. Das Herdbuch des Xalda Schafes umfasst 805 Tiere in 62 Herden. Die Population ging aus 329 Tieren hervor. Zur Zeit beträgt die Population 562 lebende Tiere und 26 aktive Herden. Die Rasse ist aufgrund der starken Nutzung weniger Individuen als Elterntiere in Gefahr, genetische Variabilität zu verlieren. Die effektive Zahl an Gründertieren ist 81,1, die an Herden 9,9. Der durchschnittliche Inzuchtkoeffizient in der gesamten Xalda Population war 1,5%. Der durchschnittliche Verwandtschaftskoeffizient (AR) erreichte 1,8% im gesamten Pedigree. Die genetische Repräsentation der Ausgangslinien ist nicht ausgewogen. Der Inzuchtzuwachs und die effektive Größe bringen aufgrund unzureichender genealogischer Daten keine realistischen Informationen bezüglich Gefährdungsstatus. Wir empfehlen eine Untersuchung der Rasse unter Verwendung von AR, um die genetischen Anteile spezifischer Individuen auszugleichen und um die unausgewogene genetische Repräsentation der Gründer und Basislinien in der Population auszugleichen. Die Verwendung von AR legt die Nutzung neuer, unterrepräsentierter Tiere in den Herden nahe, die hohe durchschnittliche AR Werte im Vergleich zur Gesamtpopulation aufweisen. Unsere Ergebnisse können für die Weiterentwicklungen von Konservierungsmaßnahmen wie offene Herdbücher nützlich sein, um das Risiko eines Verlustes genetischer Diversität durch fehlerhafte Zuchtmaßnahmen zu vermeiden. [source] The Galton,Darwin,Wedgwood Pedigree of H. H. LaughlinBIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY, Issue 1 2010TIM M. BERRA fls A pedigree of the Galton,Darwin,Wedgwood families that was exhibited as a poster at the Third International Congress of Eugenics in 1932 at the American Museum of Natural History has been located in the archives of Truman State University in Kirksville, Missouri. This pedigree was prepared by Harry Hamilton Laughlin, Director of the Eugenics Record Office of the Carnegie Institute. The pedigree shows consanguineous marriages within the three families. A special collection of rare Darwin family photographs assembled by Leonard Darwin has also been found in the Truman State University archives. These photographs were exhibited as a poster alongside the pedigree at the 1932 Eugenics Congress. The poster of the Galton,Darwin,Wedgwood pedigree is published here, together with a tabular version providing ready access to the information contained in the pedigree. Also included are the Darwin family photographs and a biographical sketch of Laughlin. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 101, 228,241. [source] Delinquent Pedigrees: Revision, Lineage, and Spatial Rhetoric in The Duchess of MalfiENGLISH LITERARY RENAISSANCE, Issue 3 2009Michelle M. Dowd Locating John Webster's The Duchess of Malfi within a cluster of early seventeenth-century concerns about legitimacy and hereditary succession, this essay traces the ways in which Webster strategically alters his primary narrative source, William Painter's The Palace of Pleasure, so as to expose rather than to suppress the indeterminacy of patrilineality. Webster's tragedy focuses specifically on a remarrying widow and her children, a particular social problem that makes visible the contradictions inherent to the early modern system of patrilineal inheritance. The action of the play thus stages the tensions between the dominant legal form of patrilineality and the material practices shaping and changing it. Drawing in part on the theories of Michel de Certeau, this essay takes a fresh critical approach to the play by placing particular emphasis on the distinctively spatialized aspects of Webster's dramaturgical rendering of his source material and noting the ways in which he uses the ideological and physical spaces of the stage to highlight the inscrutability of the succession. In addition, in its focus on Webster's revisions of Painter, the essay considers how drama as a genre can spatially reimagine the social relationships and possibilities for agency that are produced through patterns of hereditary succession. As such, The Duchess of Malfi serves as a useful case study for theorizing the narrative and dramaturgical methods by which patriarchy is constructed, contested, and reformulated in early modern English culture (M.M.D.). [source] Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy,HEPATOLOGY, Issue 1 2007Gudrun Schneider Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus and elevated bile acid serum concentrations in late pregnancy. Splicing mutations have been described in the multidrug resistance p-glycoprotein 3 (MDR3, ABCB4) gene in up to 20% of ICP women. Pedigrees studied were not large enough for linkage analysis. Ninety-seven family members of a woman with proven ICP were asked about pruritus in earlier pregnancies, birth complications and symptomatic gallstone disease. The familial cholestasis type 1 (FIC1, ATP8B1) gene, bile salt export pump (BSEP, ABCB11) and MDR3 gene were analyzed in 55 relatives. We identified a dominant mode of inheritance with female restricted expression and a new intronic MDR3 mutation c.3486+5G>A resulting in a 54 bp (3465,3518) inframe deletion via cryptic splicing site activation. Linkage analysis of the ICP trait versus this intragenic MDR3 variant yielded a LOD score of 2.48. A Bayesian analysis involving MDR3, BSEP, FIC1 and an unknown locus gave a posterior probability of >0.9966 in favor of MDR3 as causative ICP locus. During the episode of ICP the median ,-glutamyl transpeptidase (,-GT) activity was 10 U/l (95% CI, 6.9 to 14.7 U/l) in the index woman. Four stillbirths were reported in seven heterozygous women (22 pregnancies) and none in five women (14 pregnancies) without MDR3 mutation. Symptomatic gallstone disease was more prevalent in heterozygous relatives (7/21) than in relatives without the mutation (1/34), (P = 0.00341). Conclusion: This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal ,-GT and may be associated with stillbirths and gallstone disease. (HEPATOLOGY 2007;45:150,158.) [source] Genetic parameters of racing merit of thoroughbred horses in PolandJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 5 2004M. Sobczynska Summary The study aimed at estimating variance components of racing ability traits in thoroughbred horses as a contribution to defining the breeding objective for this breed. Data collected were 12 143 placings at finish (square root) and 8641 earnings (log) won by 1414 horses running in 1693 races over the period of 1998,2001. Age of horses ranged from 2 to 5+ years, and the distances were from 1000 to 3200 m. Horses were from 11 state stables, from private breeders (one collective group), and from foreign breeding (another collective group within the factor ,breeder'). Variance components were estimated by the residual maximal likelihood (REML) method. Statistical analysis accounted for fixed effects of year, age, race, breeder (optional), sex, weight carried and distance, and for the random effects of rider, permanent environment, and animal additive genetics. Pedigrees were at least three generations deep. When breeder effect was excluded from the model, heritability coefficients were 0.12 and 0.18, repeatability 0.23 and 0.34 for earnings and placings at finish, respectively. Zusammenfassung Die vorliegende Studie befasst sich mit der Varianzkomponentenschätzung für Merkmale der Rennleistung von Vollblutpferden als einen Beitrag, um die Zuchtziele näher zu definieren. Die Daten stammen aus 12143 Platzierungen (Quadratwurzel) und 8641 Gewinnsummen (Logarithmus) von 1414 Pferden in 1693 Rennen aus den Jahren 1998 bis 2001. Das Alter der Pferde reichte von zwei bis neun Jahre, die Renndistanzen von 1000 bis 3200 m. Die Pferde stammten aus 11 Ställen, von Privatzüchtern (ein gemeinsamer Zusammenschluß) und aus fremder Zucht (eine weitere zusammengeschlossene Gruppe innerhalb der Gruppe ,,Züchter''). Die Varianzkomponenten wurden mit der REML-Methode geschätzt. Die statistischen Analysen berücksichtigten als fixe Effekte Jahr, Alter, Rasse, Züchter (optional), Geschlecht, zu tragendes Gewicht und Distanz, sowie als zufällige Effekte Reiter, permanente Umwelt und der additiv genetische Tiereffekt. Die Pedigrees umfassten wenigstens drei Generationen. Ohne den Effekt des Züchters im Modell wurden für Gewinnsummen und Platzierungen Heritabilitäten von 0,12 und 0,18 sowie Wiederholbarkeiten von 0,23 und 0,34 geschätzt. [source] Generalized marker regression and interval QTL mapping methods for binary traits in half-sib family designsJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 5 2001H. N. Kadarmideen A Generalized Marker Regression Mapping (GMR) approach was developed for mapping Quantitative Trait Loci (QTL) affecting binary polygenic traits in a single-family half-sib design. The GMR is based on threshold-liability model theory and regression of offspring phenotype on expected marker genotypes at flanking marker loci. Using simulation, statistical power and bias of QTL mapping for binary traits by GMR was compared with full QTL interval mapping based on a threshold model (GIM) and with a linear marker regression mapping method (LMR). Empirical significance threshold values, power and estimates of QTL location and effect were identical for GIM and GMR when QTL mapping was restricted to within the marker interval. These results show that the theory of the marker regression method for QTL mapping is also applicable to binary traits and possibly for traits with other non-normal distributions. The linear and threshold models based on marker regression (LMR and GMR) also resulted in similar estimates and power for large progeny group sizes, indicating that LMR can be used for binary data for balanced designs with large families, as this method is computationally simpler than GMR. GMR may have a greater potential than LMR for QTL mapping for binary traits in complex situations such as QTL mapping with complex pedigrees, random models and models with interactions. Generalisierte Marker Regression und Intervall QTL Kartierungsmethoden für binäre Merkmale in einem Halbgeschwisterdesign Es wurde ein Ansatz zur generalisierten Marker Regressions Kartierung (GMR) entwickelt, um quantitative Merkmalsloci (QTL) zu kartieren, die binäre polygenetische Merkmale in einem Einfamilien-Halbgeschwisterdesign beeinflussen. Das GMR basiert auf der Theorie eines Schwellenwertmodells und auf der Regression des Nachkommenphänotyps auf den erwarteten Markergenotyp der flankierenden Markerloci. Mittels Simulation wurde die statistische Power und Schiefe der QTL Kartierung für binäre Merkmale nach GMR verglichen mit vollständiger QTL Intervallkartierung, die auf einem Schwellenmodell (GIM) basiert, und mit einer Methode zur linearen Marker Regressions Kartierung (LMR). Empirische Signifikanzschwellenwerte, Power und Schätzer für die QTL Lokation und der Effekt waren für GIM und GMR identisch, so lange die QTL Kartierung innerhalb des Markerintervalls definiert war. Diese Ergebnisse zeigen, dass die Theorie der Marker Regressions-Methode zur QTL Kartierung auch für binäre Merkmale und möglicherweise auch für Merkmale, die keiner Normalverteilung folgen, geeignet ist. Die linearen und Schwellenmodelle, die auf Marker Regression (LMR und GMR) basieren, ergaben ebenfalls ähnliche Schätzer und Power bei großen Nachkommengruppen, was schlussfolgern lässt, dass LMR für binäre Daten in einem balancierten Design mit großen Familien genutzt werden kann. Schließlich ist diese Methode computertechnisch einfacher als GMR. GMR mag für die QTL Kartierung bei binären Merkmalen in komplexen Situationen ein größeres Potential haben als LMR. Ein Beispiel dafür ist die QTL Kartierung mit komplexen Pedigrees, zufälligen Modellen und Interaktionsmodellen. [source] Variable phenotype of Alzheimer's disease with spastic paraparesisJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Helena Karlstrom Abstract Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid , peptide (A,) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid , peptide starting after the alternative ,-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity. [source] Molecular marker-based pedigrees for animal conservation biologistsANIMAL CONSERVATION, Issue 1 2010O. R. Jones Abstract Pedigrees, depicting the genealogical relationships between individuals in a population, are of fundamental importance to several research areas including conservation biology. For example, they are useful for estimating inbreeding, heritability, selection, studying kin selection and for measuring gene flow between populations. Pedigrees constructed from direct observations of reproduction are usually unavailable for wild populations. Therefore, pedigrees for these populations are usually estimated using molecular marker data. Despite their obvious importance, and the fact that pedigrees are conceptually well understood, the methods, and limitations of marker-based pedigree inference are often less well understood. Here we introduce animal conservation biologists to molecular marker-based pedigrees. We briefly describe the history of pedigree inference research, before explaining the underlying theory and basic mechanics of pedigree construction using standard methods. We explain the assumptions and limitations that accompany many of these methods, before going on to explain methods that relax several of these assumptions. Finally, we look to future and discuss some recent exciting advances such as the use of single-nucleotide polymorphisms, inference of multigenerational pedigrees and incorporation of non-genetic data such as field observations into the calculations. We also provide some guidelines on efficient marker selection in order to maximize accuracy and power. Throughout we use examples from the field of animal conservation and refer readers to appropriate software where possible. It is our hope that this review will help animal conservation biologists to understand, choose, and use the methods and tools of this fast-moving field. [source] MQScore_SNP Software for Multipoint Parametric Linkage Analysis of Quantitative Traits in Large PedigreesANNALS OF HUMAN GENETICS, Issue 3 2010Tatiana I. Axenovich Summary We describe software for multipoint parametric linkage analysis of quantitative traits using information about SNP genotypes. A mixed model of major gene and polygene inheritance is implemented in this software. Implementation of several algorithms to avoid computational underflow and decrease running time permits application of our software to the analysis of very large pedigrees collected in human genetically isolated populations. We tested our software by performing linkage analysis of adult height in a large pedigree from a Dutch isolated population. Three significant and four suggestive loci were identified with the help of our programs, whereas variance-component-based linkage analysis, which requires the pedigree fragmentation, demonstrated only three suggestive peaks. The software package MQScore_SNP is available at http://mga.bionet.nsc.ru/soft/index.html. [source] PedStr Software for Cutting Large Pedigrees for Haplotyping, IBD Computation and Multipoint Linkage AnalysisANNALS OF HUMAN GENETICS, Issue 5 2009Anatoly V. Kirichenko Summary We propose an automatic heuristic algorithm for splitting large pedigrees into fragments of no more than a user-specified bit size. The algorithm specifically aims to split large pedigrees where many close relatives are genotyped and to produce a set of sub-pedigrees for haplotype reconstruction, IBD computation or multipoint linkage analysis with the help of the Lander-Green-Kruglyak algorithm. We demonstrate that a set of overlapping pedigree fragments constructed with the help of our algorithm allows fast and effective haplotype reconstruction and detection of an allele's parental origin. Moreover, we compared pedigree fragments constructed with the help of our algorithm and existing programs PedCut and Jenti for multipoint linkage analysis. Our algorithm demonstrated significantly higher linkage power than the algorithm of Jenti and significantly shorter running time than the algorithm of PedCut. The software package PedStr implementing our algorithms is available at http://mga.bionet.nsc.ru/soft/index.html. [source] GOVERNMENT INTERVENTION IN CHILD REARING: GOVERNING INFANCYEDUCATIONAL THEORY, Issue 3 2010Robert A. Davis In this essay, Robert Davis argues that much of the moral anxiety currently surrounding children in Europe and North America emerges at ages and stages curiously familiar from traditional Western constructions of childhood. The symbolism of infancy has proven enduringly effective over the last two centuries in associating the earliest years of children's lives with a peculiar prestige and aura. Infancy is then vouchsafed within this symbolism as a state in which all of society's hopes and ideals for the young might somehow be enthusiastically invested, regardless of the complications that can be anticipated in the later, more ambivalent years of childhood and adolescence. According to Davis, the understanding of the concept of infancy associated with the rise of popular education can trace its pedigree to a genuine shift in sensibility that occurred in the middle of the eighteenth century. After exploring the essentially Romantic positions of Johann Heinrich Pestalozzi and Friedrich Fröbel and their relevance to the pattern of reform of early childhood education in the United Kingdom and the United States, Davis also assesses the influence of figures such as Stanley Hall and John Dewey in determining the rationale for modern early childhood education. A central contention of Davis's essay is that the assumptions evident in the theory and practice of Pestalozzi and his followers crystallize a series of tensions in the understanding of infancy and infant education that have haunted early childhood education from the origins of popular schooling in the late eighteenth century down to the policy dilemmas of the present day. [source] Clinical, neuropsychological, neurophysiologic, and genetic features of a new Italian pedigree with familial cortical myoclonic tremor with epilepsyEPILEPSIA, Issue 5 2009Antonio Suppa Summary We studied the clinical, neuropsychological, neurophysiologic, and genetic features of an Italian family with familial cortical myoclonic tremor with epilepsy (FCMTE). Clinically affected members of the family had limb and voice tremor, seizures, and myoclonus involving the eyelids during blinking. Neuropsychological testing disclosed visuospatial impairment, possibly due to temporal lobe dysfunction. Neurophysiologic findings suggested increased primary motor cortex excitability with normal sensorimotor integration. Linkage analysis excluded the 8q24 locus, where patients shared a common haplotype spanning 14.5 Mb in the pericentromeric region of chromosome 2. [source] An autosomal dominant genetically heterogeneous variant of rolandic epilepsy and speech disorderEPILEPSIA, Issue 6 2008Steven L. Kugler Summary We report a three generation pedigree with 11 of 22 affected with a variant form of rolandic epilepsy, speech impairment, oromotor apraxia, and cognitive deficit. The core features comprised nocturnal rolandic seizures, interictal centrotemporal spike waves with early age of onset and late age of offset. The transmission of the phenotype was consistent with autosomal dominant inheritance, with variable expressivity but no evidence of anticipation. We found evidence that the seizure and speech traits may be dissociated. No abnormalities were found by cytogenetic analysis. Linkage analysis excluded loci at 11p, 15q, 16p12, and Xq22 for related phenotypes, suggesting genetic heterogeneity. [source] Autosomal Recessive Idiopathic Epilepsy in an Inbred Family from Turkey: Identification of a Putative Locus on Chromosome 9q32-33EPILEPSIA, Issue 5 2004Betül Baykan Summary: Purpose: The study describes the clinical features of an inbred family from Turkey with three members affected by seizures and tests possible autosomal recessive (AR) inheritance by means of linkage analysis. Methods: Personal and family history was obtained from each subject, and general physical, neurologic, and EEG examinations were performed. A set of 382 fluorescence-labeled markers was used for the initial genome-wide search. A further set of 83 markers was used to map the locus precisely and to exclude the remaining genome. Results: Twelve individuals from three generations were examined. Two subjects were affected by idiopathic epilepsy, whereas, their brother experienced a single unprovoked generalized seizure. Two siblings affected by idiopathic epilepsy and their unaffected sister showed a photoparoxysmal response to photic stimulation. Nine family members reported migraine. The genome-wide search led to the identification of a unique homozygous, 15.1-cM region shared by subjects with seizures on chromosome 9q32-33 and providing a lod score of 2.9. This locus, however, was not associated with migraine in this pedigree. Conclusions: The study suggests that idiopathic epileptic traits with AR inheritance might be underestimated in the general population and that inbred pedigrees may represent powerful tools for the identification of AR genes. [source] EVOLUTIONARY POTENTIAL OF A LARGE MARINE VERTEBRATE: QUANTITATIVE GENETIC PARAMETERS IN A WILD POPULATIONEVOLUTION, Issue 4 2009Joseph D. DiBattista Estimating quantitative genetic parameters ideally takes place in natural populations, but relatively few studies have overcome the inherent logistical difficulties. For this reason, no estimates currently exist for the genetic basis of life-history traits in natural populations of large marine vertebrates. And yet such estimates are likely to be important given the exposure of this taxon to changing selection pressures, and the relevance of life-history traits to population productivity. We report such estimates from a long-term (1995,2007) study of lemon sharks (Negaprion brevirostris) conducted at Bimini, Bahamas. We obtained these estimates by genetically reconstructing a population pedigree (117 dams, 487 sires, and 1351 offspring) and then using an "animal model" approach to estimate quantitative genetic parameters. We find significant additive genetic (co)variance, and hence moderate heritability, for juvenile length and mass. We also find substantial maternal effects for these traits at age-0, but not age-1, confirming that genotype,phenotype interactions between mother and offspring are strongest at birth; although these effects could not be parsed into their genetic and nongenetic components. Our results suggest that human-imposed selection pressures (e.g., size-selective harvesting) might impose noteworthy evolutionary change even in large marine vertebrates. We therefore use our findings to explain how maternal effects may sometimes promote maladaptive juvenile traits, and how lemon sharks at different nursery sites may show "constrained local adaptation." We also show how single-generation pedigrees, and even simple marker-based regression methods, can provide accurate estimates of quantitative genetic parameters in at least some natural systems. [source] A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutationGENES, CHROMOSOMES AND CANCER, Issue 1 2005Anders Molven Mutations in two loci encoding cell-cycle-regulatory proteins have been shown to cause familial malignant melanoma. About 20% of melanoma-prone families bear a mutation in the CDKN2A locus, which encodes two unrelated proteins, p16INK4A and p14ARF. Mutations in the other locus, CDK4, are much rarer and have been linked to the disease in only three families worldwide. In the 1960s, a large Norwegian pedigree with multiple atypical nevi and malignant melanomas was identified. Subsequently, six generations and more than 100 family members were traced and 20 cases of melanoma verified. In this article, we report that CDK4 codon 24 is mutated from CGT to CAT (Arg24His) in this unusually large melanoma kindred. Intriguingly, one of the family members had ocular melanoma, but the CDK4 mutation could not be detected in archival tissue samples from this subject. Thus, the case of ocular melanoma in this family was sporadic, suggesting an etiology different from that of the skin tumors. The CDK4 mutation in the Norwegian family was identical to that in melanoma families in France, Australia, and England. Haplotype analysis using microsatellite markers flanking the CDK4 gene and single-nucleotide polymorphisms within the gene did not support the possibility that there was a common founder, but rather indicated at least two independent mutational events. All CDK4 melanoma families known to date have a substitution of amino acid 24. In addition to resulting from selection pressure, this observation may be explained by the CG dinucleotide of codon 24 representing a mutational hot spot in the CDK4 gene. © 2005 Wiley-Liss, Inc. [source] Assessment of SNP streak statistics using gene drop simulation with linkage disequilibriumGENETIC EPIDEMIOLOGY, Issue 2 2010Alun ThomasArticle first published online: 6 JUL 200 Abstract We describe methods and programs for simulating the genotypes of individuals in a pedigree at large numbers of linked loci when the alleles of the founders are under linkage disequilibrium. Both simulation and estimation of linkage disequilibrium models are shown to be feasible on a genome wide scale. The methods are applied to evaluate the statistical significance of streaks of loci at which sets of related individuals share a common allele. The effects of properly allowing for linkage disequilibrium are shown to be important as they explain many of the large observations. This is illustrated by reanalysis of a previously reported linkage of prostate cancer to chromosome 1p23. Genet. Epidemiol. 34: 119,124, 2010. © 2009 Wiley-Liss, Inc. [source] Case-control association testing in the presence of unknown relationshipsGENETIC EPIDEMIOLOGY, Issue 8 2009Yoonha Choi Abstract Genome-wide association studies result in inflated false-positive results when unrecognized cryptic relatedness exists. A number of methods have been proposed for testing association between markers and disease with a correction for known pedigree-based relationships. However, in most case-control studies, relationships are generally unknown, yet the design is predicated on the assumption of at least ancestral relatedness among cases. Here, we focus on adjusting cryptic relatedness when the genealogy of the sample is unknown, particularly in the context of samples from isolated populations where cryptic relatedness may be problematic. We estimate cryptic relatedness using maximum-likelihood methods and use a corrected ,2 test with estimated kinship coefficients for testing in the context of unknown cryptic relatedness. Estimated kinship coefficients characterize precisely the relatedness between truly related people, but are biased for unrelated pairs. The proposed test substantially reduces spurious positive results, producing a uniform null distribution of P -values. Especially with missing pedigree information, estimated kinship coefficients can still be used to correct non-independence among individuals. The corrected test was applied to real data sets from genetic isolates and created a distribution of P -value that was close to uniform. Thus, the proposed test corrects the non-uniform distribution of P -values obtained with the uncorrected test and illustrates the advantage of the approach on real data. Genet. Epidemiol. 33:668,678, 2009. © 2009 Wiley-Liss, Inc. [source] Replication of genetic associations as pseudoreplication due to shared genealogyGENETIC EPIDEMIOLOGY, Issue 6 2009Noah A. Rosenberg Abstract The genotypes of individuals in replicate genetic association studies have some level of correlation due to shared descent in the complete pedigree of all living humans. As a result of this genealogical sharing, replicate studies that search for genotype-phenotype associations using linkage disequilibrium between marker loci and disease-susceptibility loci can be considered as "pseudoreplicates" rather than true replicates. We examine the size of the pseudoreplication effect in association studies simulated from evolutionary models of the history of a population, evaluating the excess probability that both of a pair of studies detect a disease association compared to the probability expected under the assumption that the two studies are independent. Each of nine combinations of a demographic model and a penetrance model leads to a detectable pseudoreplication effect, suggesting that the degree of support that can be attributed to a replicated genetic association result is less than that which can be attributed to a replicated result in a context of true independence. Genet. Epidemiol. 33:479,487, 2009. © 2009 Wiley-Liss, Inc. [source] A multiple splitting approach to linkage analysis in large pedigrees identifies a linkage to asthma on chromosome 12GENETIC EPIDEMIOLOGY, Issue 3 2009Céline Bellenguez Abstract Large genealogies are potentially very informative for linkage analysis. However, the software available for exact non-parametric multipoint linkage analysis is limited with respect to the complexity of the families it can handle. A solution is to split the large pedigrees into sub-families meeting complexity constraints. Different methods have been proposed to "best" split large genealogies. Here, we propose a new procedure in which linkage is performed on several carefully chosen sub-pedigree sets from the genealogy instead of using just a single sub-pedigree set. Our multiple splitting procedure capitalizes on the sensitivity of linkage results to family structure and has been designed to control computational feasibility and global type I error. We describe and apply this procedure to the extreme case of the highly complex Hutterite pedigree and use it to perform a genome-wide linkage analysis on asthma. The detection of a genome-wide significant linkage for asthma on chromosome 12q21 illustrates the potential of this multiple splitting approach. Genet. Epidemiol. 2009. © 2008 Wiley-Liss, Inc. [source] Bivariate combined linkage and association mapping of quantitative trait lociGENETIC EPIDEMIOLOGY, Issue 5 2008Jeesun Jung Abstract In this paper, bivariate/multivariate variance component models are proposed for high-resolution combined linkage and association mapping of quantitative trait loci (QTL), based on combinations of pedigree and population data. Suppose that a quantitative trait locus is located in a chromosome region that exerts pleiotropic effects on multiple quantitative traits. In the region, multiple markers such as single nucleotide polymorphisms are typed. Two regression models, "genotype effect model" and "additive effect model", are proposed to model the association between the markers and the trait locus. The linkage information, i.e., recombination fractions between the QTL and the markers, is modeled in the variance and covariance matrix. By analytical formulae, we show that the "genotype effect model" can be used to model the additive and dominant effects simultaneously; the "additive effect model" only takes care of additive effect. Based on the two models, F -test statistics are proposed to test association between the QTL and markers. By analytical power analysis, we show that bivariate models can be more powerful than univariate models. For moderate-sized samples, the proposed models lead to correct type I error rates; and so the models are reasonably robust. As a practical example, the method is applied to analyze the genetic inheritance of rheumatoid arthritis for the data of The North American Rheumatoid Arthritis Consortium, Problem 2, Genetic Analysis Workshop 15, which confirms the advantage of the proposed bivariate models. Genet. Epidemiol. 2008. © 2008 Wiley-Liss, Inc. [source] Relationship uncertainty linkage statistics (RULS): affected relative pair statistics that model relationship uncertaintyGENETIC EPIDEMIOLOGY, Issue 4 2008Amrita Ray Abstract Linkage analysis programs invariably assume that the stated familial relationships are correct. Thus, it is common practice to resolve relationship errors by either discarding individuals with erroneous relationships or using an inferred alternative pedigree structure. These approaches are less than ideal because discarding data is wasteful and using inferred data can be statistically unsound. We have developed two linkage statistics that model relationship uncertainty by weighting over the possible true relationships. Simulations of data containing relationship errors were used to assess our statistics and compare them to the maximum-likelihood statistic (MLS) and the Sall non-parametric LOD score using true and discarded (where problematic individuals with erroneous relationships are discarded from the pedigree) structures. We simulated both small pedigree (SP) and large pedigree (LP) data sets typed genome-wide. Both data sets have several underlying true relationships; SP has one apparent relationship,full sibling,and LP has several different apparent relationship types. The results show that for both SP and LP, our relationship uncertainty linkage statistics (RULS) have power nearly as high as the MLS and Sall using the true structure. Also, the RULS have greater power to detect linkage than the MLS and Sall using the discarded structure. For example, for the SP data set and a dominant disease model, both the RULS had power of about 93%, while Sall and MLS have 90% and 83% power on the discarded structure. Thus, our RULS provide a statistically sound and powerful approach to the commonly encountered problem of relationship errors. Genet. Epidemiol. © 2008 Wiley-Liss, Inc. [source] Estimating the power of variance component linkage analysis in large pedigreesGENETIC EPIDEMIOLOGY, Issue 6 2006Wei-Min Chen Abstract Variance component linkage analysis is commonly used to map quantitative trait loci (QTLs) in general pedigrees. Large pedigrees are especially attractive for these studies because they provide greater power per genotyped individual than small pedigrees. We propose accurate and computationally efficient methods to calculate the analytical power of variance component linkage analysis that can accommodate large pedigrees. Our analytical power computation involves the approximation of the noncentrality parameter for the likelihood-ratio test by its Taylor expansions. We develop efficient algorithms to compute the second and third moments of the identical by descent (IBD) sharing distribution and enable rapid computation of the Taylor expansions. Our algorithms take advantage of natural symmetries in pedigrees and can accurately analyze many large pedigrees in a few seconds. We verify the accuracy of our power calculation via simulation in pedigrees with 2,5 generations and 2,8 siblings per sibship. We apply this proposed analytical power calculation to 98 quantitative traits in a cohort study of 6,148 Sardinians in which the largest pedigree includes 625 phenotyped individuals. Simulations based on eight representative traits show that the difference between our analytical estimation of the expected LOD score and the average of simulated LOD scores is less than 0.05 (1.5%). Although our analytical calculations are for a fully informative marker locus, in the settings we examined power was similar to what could be attained with a single nucleotide polymorphism (SNP) mapping panel (with >1 SNP/cM). Our algorithms for power analysis together with polygenic analysis are implemented in a freely available computer program, POLY. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Linkage mapping methods applied to the COGA data set: Presentation Group 4 of Genetic Analysis Workshop 14GENETIC EPIDEMIOLOGY, Issue S1 2005E. Warwick Daw Abstract Presentation Group 4 participants analyzed the Collaborative Study on the Genetics of Alcoholism data provided for Genetic Analysis Workshop 14. This group examined various aspects of linkage analysis and related issues. Seven papers included linkage analyses, while the eighth calculated identity-by-descent (IBD) probabilities. Six papers analyzed linkage to an alcoholism phenotype: ALDX1 (four papers), ALDX2 (one paper), or a combination both (one paper). Methods used included Bayesian variable selection coupled with Haseman-Elston regression, recursive partitioning to identify phenotype and covariate groupings that interact with evidence for linkage, nonparametric linkage regression modeling, affected sib-pair linkage analysis with discordant sib-pair controls, simulation-based homozygosity mapping in a single pedigree, and application of a propensity score to collapse covariates in a general conditional logistic model. Alcoholism linkage was found with ,2 of these approaches on chromosomes 2, 4, 6, 7, 9, 14, and 21. The remaining linkage paper compared the utility of several single-nucleotide polymorphism (SNP) and microsatellite marker maps for Monte Carlo Markov chain combined oligogenic segregation and linkage analysis, and analyzed one of the electrophysiological endophenotypes, ttth1, on chromosome 7. Linkage was found with all marker sets. The last paper compared the multipoint IBD information content of several SNP sets and the microsatellite set, and found that while all SNP sets examined contained more information than the microsatellite set, most of the information contained in the SNP sets was captured by a subset of the SNP markers with ,1-cM marker spacing. From these papers, we highlight three points: a 1-cM SNP map seems to capture most of the linkage information, so denser maps do not appear necessary; careful and appropriate use of covariates can aid linkage analysis; and sources of increased gene-sharing between relatives should be accounted for in analyses. Genet. Epidemiol. 29(Suppl. 1):S29,S34, 2005. © 2005 Wiley-Liss, Inc. [source] Case-control single-marker and haplotypic association analysis of pedigree dataGENETIC EPIDEMIOLOGY, Issue 2 2005Sharon R. Browning Abstract Related individuals collected for use in linkage studies may be used in case-control linkage disequilibrium analysis, provided one takes into account correlations between individuals due to identity-by-descent (IBD) sharing. We account for these correlations by calculating a weight for each individual. The weights are used in constructing a composite likelihood, which is maximized iteratively to form likelihood ratio tests for single-marker and haplotypic associations. The method scales well with increasing pedigree size and complexity, and is applicable to both autosomal and X chromosomes. We apply the approach to an analysis of association between type 2 diabetes and single-nucleotide polymorphism markers in the PPAR-, gene. Simulated data are used to check validity of the test and examine power. Analysis of related cases has better power than analysis of population-based cases because of the increased frequencies of disease-susceptibility alleles in pedigrees with multiple cases compared to the frequencies of these alleles in population-based cases. Also, utilizing all cases in a pedigree rather than just one per pedigree improves power by increasing the effective sample size. We demonstrate that our method has power at least as great as that of several competing methods, while offering advantages in the ability to handle missing data and perform haplotypic analysis. Genet. Epidemiol. 28:110,122, 2005. © 2004 Wiley-Liss, Inc. [source] Efficient Simulation of P Values for Linkage AnalysisGENETIC EPIDEMIOLOGY, Issue 2 2004Kyunghee K. Song Abstract In many genetic linkage analyses, the P value is obtained through simulation since the underlying distribution of the test statistic is complex and unknown. However, this can be very computationally intensive. A "bootstrap/replicate pool" approach has been suggested that generates P values more efficiently in terms of computation by resampling sums from a small set of simulated replicates for each pedigree. The replicate pool idea has been successfully applied, but, to our knowledge, has never been theoretically studied. An entirely different method for increasing the computational efficiency of P value simulation is Besag and Clifford's sequential sampling method. We propose an algorithm which combines Besag and Clifford's method with the replicate pool method to efficiently estimate P values for linkage studies. We derive variance expressions for the P value estimates from the replicate pool method and from our proposed hybrid method, and use these to show that the hybrid estimator has a substantial advantage over the other methods in most situations. Genet Epidemiol 26: 88,96, 2004. © 2004 Wiley-Liss, Inc. [source] Finding starting points for Markov chain Monte Carlo analysis of genetic data from large and complex pedigreesGENETIC EPIDEMIOLOGY, Issue 1 2003Yuqun Luo Abstract Genetic data from founder populations are advantageous for studies of complex traits that are often plagued by the problem of genetic heterogeneity. However, the desire to analyze large and complex pedigrees that often arise from such populations, coupled with the need to handle many linked and highly polymorphic loci simultaneously, poses challenges to current standard approaches. A viable alternative to solving such problems is via Markov chain Monte Carlo (MCMC) procedures, where a Markov chain, defined on the state space of a latent variable (e.g., genotypic configuration or inheritance vector), is constructed. However, finding starting points for the Markov chains is a difficult problem when the pedigree is not single-locus peelable; methods proposed in the literature have not yielded completely satisfactory solutions. We propose a generalization of the heated Gibbs sampler with relaxed penetrances (HGRP) of Lin et al., ([1993] IMA J. Math. Appl. Med. Biol. 10:1,17) to search for starting points. HGRP guarantees that a starting point will be found if there is no error in the data, but the chain usually needs to be run for a long time if the pedigree is extremely large and complex. By introducing a forcing step, the current algorithm substantially reduces the state space, and hence effectively speeds up the process of finding a starting point. Our algorithm also has a built-in preprocessing procedure for Mendelian error detection. The algorithm has been applied to both simulated and real data on two large and complex Hutterite pedigrees under many settings, and good results are obtained. The algorithm has been implemented in a user-friendly package called START. Genet Epidemiol 25:14,24, 2003. © 2003 Wiley-Liss, Inc. [source] Using a minigene approach to characterize a novel splice site mutation in human F7 gene causing inherited factor VII deficiency in a Chinese pedigreeHAEMOPHILIA, Issue 6 2009T. YU Summary., Factor VII deficiency which transmitted as an autosomal recessive disorder is a rare haemorrhagic condition. The aim of this study was to identify the molecular genetic defect and determine its functional consequences in a Chinese pedigree with FVII deficiency. The proband was diagnosed as inherited coagulation FVII deficiency by reduced plasma levels of FVII activity (4.4%) and antigen (38.5%). All nine exons and their flanking sequence of F7 gene were amplified by polymerase chain reaction (PCR) for the proband and the PCR products were directly sequenced. The compound heterozygous mutations of F7 (NM_000131.3) c.572-1G>A and F7 (NM_000131.3) c.1165T>G; p.Cys389Gly were identified in the proband's F7 gene. To investigate the splicing patterns associated with F7 c.572-1G>A, ectopic transcripts in leucocytes of the proband were analyzed. F7 minigenes, spanning from intron 4 to intron 7 and carrying either an A or a G at position -1 of intron 5, were constructed and transiently transfected into human embryonic kidney (HEK) 293T cells, followed by RT-PCR analysis. The aberrant transcripts from the F7 c.572-1G>A mutant allele were not detected by ectopic transcription study. Sequencing of the RT-PCR products from the mutant transfectant demonstrated the production of an erroneously spliced mRNA with exon 6 skipping, whereas a normal splicing occurred in the wide type transfectant. The aberrant mRNA produced from the F7 c.572-1G>A mutant allele is responsible for the factor VII deficiency in this pedigree. [source] Variability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C,T mutationHAEMOPHILIA, Issue 1 2009A. SHARATHKUMAR Summary., The aim of this study was to characterize the variability of bleeding phenotype and its association with plasma factor IX coagulant activity (FIX:C) in haemophilia B carriers in a large Amish pedigree with a unifying genetic mutation, C-to-T transition at base 31008 of the factor IX gene (Xq27.1,27.2). A cross-sectional survey of haemophilia B carriers included a multiple choice questionnaire evaluating symptoms of mucocutaneous bleeding, joint bleeding and bleeding after haemostatic stress [menstruation, postpartum haemorrhage (PPH), dental extractions and invasive surgeries]. Severity of bleeding was graded as 0 to 4, 0 being no bleeding whereas 4 being severe bleeding. Association between total bleeding scores and the FIX:C was evaluated. Sixty-four haemophilia B carriers participated in this study. Median age: 18 years (range 1,70 years); median bleeding score: 1 (range 0,8). Besides PPH, isolated symptoms of bruising, epistaxis, menorrhagia and postsurgical bleeding including dental extraction were not associated with lower FIX:C. Bleeding score ,3 was associated with involvement of at least two bleeding sites and a lower mean FIX:C of 42 ± 10.3% (95% CI 36.4,47.7) while a score >3 had involvement of ,2 sites and higher mean FIX:C of 54.9 ± 21.5% (95% CI 49,61), P = 0.005. Subcutaneous haematoma formation and bleeding after haemostatic stress requiring treatment were associated with bleeding scores ,3. Phenotypic variability existed among the carriers of haemophilia B who belonged to a single pedigree carrying a single unifying mutation. The utility of bleeding scores to define bleeding phenotype precisely in haemophilia B carriers needs further evaluation. [source] | ||||||||||||||||||||||||||||||||||