A Longitudinal Study of Stargardt Disease: Quantitative Assessment of Fundus Autofluorescence, Progression and Genotype Correlations

PURPOSE To characterise subtypes of fundus autofluorescence (AF), the progression of retinal atrophy and correlate these findings with genotype in Stargardt Disease. METHODS Full clinical examination and AF imaging was undertaken in 68 patients with Stargardt Disease. The baseline data were compared with those at follow-up. Patients were classified into three AF subtypes: type 1 had a localised low signal at the fovea surrounded by a homogeneous background; type 2 had a localised low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal; type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm2) divided by the follow-up interval (yrs). Molecular screening of ABCA4 was undertaken. RESULTS The mean follow-up interval was 9.1 years. 42% of type 1 progressed to type 2, and 12% of type 2 progressed to type 3. RAE (mm2/yr) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype. CONCLUSIONS The AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counselling on prognosis in Stargardt Disease and be valuable for future clinical trials.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2sigma;2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2sigma;2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca<inf>o</inf>²⁺) homeostasis. To elucidate the role of AP2sigma;2 in Ca<inf>o</inf>²⁺ regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2sigma;2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2sigma;2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2sigma;2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2sigma;2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2sigma;2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Genome wide search for genetic determinants of habitual alcohol, tobacco and coffee use, obesity-related traits, response to mental and physical stress and hemodynamic traits

Les habitudes de consommation de substances psychoactives, le stress, l’obésité et les traits cardiovasculaires associés seraient en partie reliés aux mêmes facteurs génétiques. Afin d’explorer cette hypothèse, nous avons effectué, chez 119 familles multi-générationnelles québécoises de la région du Saguenay-Lac-St-Jean, des études d’association et de liaison pangénomiques pour les composantes génétiques : de la consommation usuelle d’alcool, de tabac et de café, de la réponse au stress physique et psychologique, des traits anthropométriques reliés à l’obésité, ainsi que des mesures du rythme cardiaque (RC) et de la pression artérielle (PA). 58000 SNPs et 437 marqueurs microsatellites ont été utilisés et l’annotation fonctionnelle des gènes candidats identifiés a ensuite été réalisée. Nous avons détecté des corrélations phénotypiques significatives entre les substances psychoactives, le stress, l’obésité et les traits hémodynamiques. Par exemple, les consommateurs d’alcool et de tabac ont montré un RC significativement diminué en réponse au stress psychologique. De plus, les consommateurs de tabac avaient des PA plus basses que les non-consommateurs. Aussi, les hypertendus présentaient des RC et PA systoliques accrus en réponse au stress psychologique et un indice de masse corporelle (IMC) élevé, comparativement aux normotendus. D’autre part, l’utilisation de tabac augmenterait les taux corporels d’épinéphrine, et des niveaux élevés d’épinéphrine ont été associés à des IMC diminués. Ainsi, en accord avec les corrélations inter-phénotypiques, nous avons identifié plusieurs gènes associés/liés à la consommation de substances psychoactives, à la réponse au stress physique et psychologique, aux traits reliés à l’obésité et aux traits hémodynamiques incluant CAMK4, CNTN4, DLG2, DAG1, FHIT, GRID2, ITPR2, NOVA1, NRG3 et PRKCE. Ces gènes codent pour des protéines constituant un réseau d’interactions, impliquées dans la plasticité synaptique, et hautement exprimées dans le cerveau et ses tissus associés. De plus, l’analyse des sentiers de signalisation pour les gènes identifiés (P = 0,03) a révélé une induction de mécanismes de Potentialisation à Long Terme. Les variations des traits étudiés seraient en grande partie liées au sexe et au statut d’hypertension. Pour la consommation de tabac, nous avons noté que le degré et le sens des corrélations avec l’obésité, les traits hémodynamiques et le stress sont spécifiques au sexe et à la pression artérielle. Par exemple, si des variations ont été détectées entre les hommes fumeurs et non-fumeurs (anciens et jamais), aucune différence n’a été observée chez les femmes. Nous avons aussi identifié de nombreux traits reliés à l’obésité dont la corrélation avec la consommation de tabac apparaît essentiellement plus liée à des facteurs génétiques qu’au fait de fumer en lui-même. Pour le sexe et l’hypertension, des différences dans l’héritabilité de nombreux traits ont également été observées. En effet, des analyses génétiques sur des sous-groupes spécifiques ont révélé des gènes additionnels partageant des fonctions synaptiques : CAMK4, CNTN5, DNM3, KCNAB1 (spécifique à l’hypertension), CNTN4, DNM3, FHIT, ITPR1 and NRXN3 (spécifique au sexe). Ces gènes codent pour des protéines interagissant avec les protéines de gènes détectés dans l’analyse générale. De plus, pour les gènes des sous-groupes, les résultats des analyses des sentiers de signalisation et des profils d’expression des gènes ont montré des caractéristiques similaires à celles de l’analyse générale. La convergence substantielle entre les déterminants génétiques des substances psychoactives, du stress, de l’obésité et des traits hémodynamiques soutiennent la notion selon laquelle les variations génétiques des voies de plasticité synaptique constitueraient une interface commune avec les différences génétiques liées au sexe et à l’hypertension. Nous pensons, également, que la plasticité synaptique interviendrait dans de nombreux phénotypes complexes influencés par le mode de vie. En définitive, ces résultats indiquent que des approches basées sur des sous-groupes et des réseaux amélioreraient la compréhension de la nature polygénique des phénotypes complexes, et des processus moléculaires communs qui les définissent.

Making development simple. The genetic deterministic hypothesis for economic development

This paper discusses the dangers inherent in allempting to simplify something as complex as development. It does this by exploring the Lynn and Vanhanen theory of deterministic development which asserts that varying levels of economic development seen between countries can be explained by differences in 'national intelligence' (national IQ). Assuming that intelligence is genetically determined, and as different races have been shown to have different IQ, then they argue that economic development (measured as GDP/capita) is largely a function of race and interventions to address imbalances can only have a limited impact. The paper presents the Lynne and Vanhanen case and critically discusses the data and analyses (linear regression) upon which it is based. It also extends the cause-effect basis of Lynne and Vanhanen's theory for economic development into human development by using the Human Development Index (HDI). It is argued that while there is nothing mathematically incorrect with their calculations, there are concerns over the data they employ. Even more fundamentally it is argued that statistically significant correlations between the various components of the HDI and national IQ can occur via a host of cause-effect pathways, and hence the genetic determinism theory is far from proven. The paper ends by discussing the dangers involved in the use of over-simplistic measures of development as a means of exploring cause-effect relationships. While the creators of development indices such as the HDI have good intentions, simplistic indices can encourage simplistic explanations of under-development. (c) 2005 Elsevier B.V. All rights reserved.

Comparing correlations of continuous observations from two independent populations using a sequential approach

A sequential study design generally makes more efficient use of available information than a fixed sample counterpart of equal power. This feature is gradually being exploited by researchers in genetic and epidemiological investigations that utilize banked biological resources and in studies where time, cost and ethics are prominent considerations. Recent work in this area has focussed on the sequential analysis of matched case-control studies with a dichotomous trait. In this paper, we extend the sequential approach to a comparison of the associations within two independent groups of paired continuous observations. Such a comparison is particularly relevant in familial studies of phenotypic correlation using twins. We develop a sequential twin method based on the intraclass correlation and show that use of sequential methodology can lead to a substantial reduction in the number of observations without compromising the study error rates. Additionally, our approach permits straightforward allowance for other explanatory factors in the analysis. We illustrate our method in a sequential heritability study of dysplasia that allows for the effect of body mass index and compares monozygotes with pairs of singleton sisters. Copyright (c) 2006 John Wiley & Sons, Ltd.

The role of the international cocoa germplasm database and the international cocoa quarantine centre in information management and distribution of cocoa genetic resources

A range of physiological parameters (canopy light transmission, canopy shape, leaf size, flowering and flushing intensity) were measured from the International Clone Trial, typically over the course of two years. Data were collected from six locations, these being: Brazil, Ecuador, Trinidad, Venezuela, Côte d’Ivoire and Ghana. Canopy shape varied significantly between clones, although it showed little variation between locations. Genotypic variation in leaf size was differentially affected by the growth location; such differences appeared to underlie a genotype by environment interaction in relation to canopy light transmission. Flushing data were recorded at monthly intervals over the course of a year. Within each location, a significant interaction was observed between genotype and time of year, suggesting that some genotypes respond to a greater extent than others to environmental stimuli. A similar interaction was observed for flowering data, where significant correlations were found between flowering intensity and temperature in Brazil and flowering intensity and rainfall in Côte d’Ivoire. The results demonstrate the need for local evaluation of cocoa clones and also suggest that the management practices for particular planting material may need to be fine-tuned to the location in which they are cultivated.

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease- causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15. Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson’s disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes.

Sex-dependent selection differentially shapes genetic variation on and off the guppy Y chromosome

Because selection is often sex-dependent, alleles can have positive effects on fitness in one sex and negative effects in the other, resulting in intralocus sexual conflict. Evolutionary theory predicts that intralocus sexual conflict can drive the evolution of sex limitation, sex-linkage, and sex chromosome differentiation. However, evidence that sex-dependent selection results in sex-linkage is limited. Here, we formally partition the contribution of Y-linked and non-Y-linked quantitative genetic variation in coloration, tail, and body size of male guppies (Poecilia reticulata)—traits previously implicated as sexually antagonistic. We show that these traits are strongly genetically correlated, both on and off the Y chromosome, but that these correlations differ in sign and magnitude between both parts of the genome. As predicted, variation in attractiveness was found to be associated with the Y-linked, rather than with the non-Y-linked component of genetic variation in male ornamentation. These findings show how the evolution of Y-linkage may be able to resolve sexual conflict. More generally, they provide unique insight into how sex-specific selection has the potential to differentially shape the genetic architecture of fitness traits across different parts of the genome.

Estimates of genetic parameters for visual scores and daily weight gain in Brangus animals

(Co) variance components were estimated for visual scores of conformation (CY), early finishing (PY) and muscling (MY) at 550 days of age (yearling), average daily gain from weaning to yearling (GWY), conformation (CW), early finishing (PW) and muscling (MW) scores at weaning, and average daily gain from birth to weaning (GBW) in animals forming the Brazilian Brangus breed born between 1986 and 2002 from the livestock files of GenSys Consultants Associados S/C Ltda. The data set contained 53 683; 45 136; 52 937; 56 471; 24 531; 21 166; 24 006 and 25 419 records for CW, PW, MW, GBW, CY, PY, MY and GWY, respectively. Data were analyzed by the restricted maximum likelihood method using single-and two-trait animal models. Direct heritability estimates obtained by single-trait analysis were 0.12, 0.14, 0.13 and 0.14 for CY, PY and MY scores and GWY, respectively. A positive association was observed between the same visual scores at weaning and yearling, with correlations ranging from 0.64 to 0.94. Estimated correlations between GBW and weaning and yearling scores ranged from 0.60 to 0.77. The genetic correlation between GBW and GWY was low (0.10), whereas correlations of 0.55, 0.37 and 0.47 were observed between GWY and CY, PY and MY, respectively. Moreover, GWY showed a weak correlation with CW (0.10), PW (-0.08) and MW (-0.03) scores. These results indicate that selection of the traits that was studied would result in a small response. In addition, selection based on average daily gain may have an indirect effect on visual scores as the correlations between GWY and visual scores were generally strong.

Genetic analysis on growth and carcass traits in Nelore cattle

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Generalized linear mixed models for the genetic evaluation of binary reproductive traits: a simulation study

The objective of this study was to evaluate the use of probit and logit link functions for the genetic evaluation of early pregnancy using simulated data. The following simulation/analysis structures were constructed: logit/logit, logit/probit, probit/logit, and probit/probit. The percentages of precocious females were 5, 10, 15, 20, 25 and 30% and were adjusted based on a change in the mean of the latent variable. The parametric heritability (h²) was 0.40. Simulation and genetic evaluation were implemented in the R software. Heritability estimates (ĥ²) were compared with h² using the mean squared error. Pearson correlations between predicted and true breeding values and the percentage of coincidence between true and predicted ranking, considering the 10% of bulls with the highest breeding values (TOP10) were calculated. The mean ĥ² values were under- and overestimated for all percentages of precocious females when logit/probit and probit/logit models used. In addition, the mean squared errors of these models were high when compared with those obtained with the probit/probit and logit/logit models. Considering ĥ², probit/probit and logit/logit were also superior to logit/probit and probit/logit, providing values close to the parametric heritability. Logit/probit and probit/logit presented low Pearson correlations, whereas the correlations obtained with probit/probit and logit/logit ranged from moderate to high. With respect to the TOP10 bulls, logit/probit and probit/logit presented much lower percentages than probit/probit and logit/logit. The genetic parameter estimates and predictions of breeding values of the animals obtained with the logit/logit and probit/probit models were similar. In contrast, the results obtained with probit/logit and logit/probit were not satisfactory. There is need to compare the estimation and prediction ability of logit and probit link functions.

Genetic parameters for milk, fat and protein yields in Murrah buffaloes (Bubalus bubalis Artiodactyla, Bovidae)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Genetic associations between flight speed and growth traits in Nellore cattle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Genetic associations between stayability and reproductive and growth traits in Canchim beef cattle

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Estimation of genetic parameters for milk yield in Murrah buffaloes by Bayesian inference

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)