The genetic fine structure of nonsense suppressors in Schizosaccharomyces pombe

Summary Meiotic and mitotic fine-structure maps of two efficient UGA suppressors of Schizosaccharomyces pombe which are known (sup3-e) or inferred (sup9-e) to code for two serine tRNAs carrying the mutant anticodon U*CA (Kohli et al. 1979a, b, Rafalski et al. 1979) are presented. Maps based on spontaneous meiotic, spontaneous mitotic and MMS induced mitotic recombination between the primary site of the anticodon mutation and a number of inactivating second-site mutations are similar. Specific marker effects, which drastically increase the frequency of spontaneous meiotic and mitotic recombination in crosses involving one or the other of four exceptional sites (including the anticodon sites of both sup3-e and sup9-e), disappear when mapping is based on MMS induced mitotic recombination. The meiotic marker effect characterizing the anticodon site of one of the two efficient UGA suppressors (sup3-e) also disappears upon further mutation to an inefficient UAA suppressor allele (sup3-i), as shown by its absence in a fine-structure map based on meiotic recombination between the anticodon mutation of this ochre suppressor allele and a new set of inactivating second-site mutations derived from it.     

The genetic fine structure of nonsense suppressors in Schizosaccharomyces pombe

Summary Meiotic fine-structure maps of two efficient UGA suppressors of Schizosaccharomyces pombe which are known (sup8-e) or inferred (sup10-e) to code for two leucine tRNAs carrying the mutant anticodon U^*CA (Kohli et al. 1979, 1980a, b; Wetzel et al. 1979; Mao et al. 1981) are presented. In both cases, the recombination frequencies given by the primary site of the anticodon mutation fitwell into the map defined by the sites of a number of inactivating secondary mutations. This contrasts the corresponding situation found in the serine tRNA genes sup3 and sup9 where the anticodon site exhibits a specific marker effect which strongly increases recombination frequencies in crosses with all revertant sites, due to a decrease in the efficiency of excision repair of base-pair mismatches whenever the anticodon site is included in hybrid-DNA (Hofer et al. 1979; Munz and Leupold 1979; Thuriaux et al. 1980). A pronounced specific marker effect which leads to a several fold increase of the recombination frequencies over those expected is observed, however, at one of the secondary inactivating sites mapping in the leucine tRNA gene sup8.     

The paternal genetic structure of Jingpo and Dai in southwest China

Yunnan province harbours substantial genetic, cultural and linguistic diversity, with the largest number of Aborigines in China, but the relationship among these Aborigines remains enigmatic. This study genotyped 45 Y chromosomal single nucleotide polymorphisms (SNPs) of 500 males from two aboriginal cross-border populations, Jingpo and Dai, from Dehong, Yunnan. It is reported that Haplogroup O2a2b1a1-M117 is the dominant lineage in both Jingpo and Dai. The Jingpo people show affinity with Tibeto-Burman speaking populations with a relatively high frequency of Haplogroup D-M174, and the Dai people are generally genetically similar with Tai-Kadai speaking populations with high frequencies of Haplogroup O1a-M119 and O1b1a1a-M95, which is consistent with their language classification.     

The origins of the Irish travellers and the genetic structure of Ireland

Ireland's unique and well-documented history provides insight into the formation and origins of population subdivisions. Of particular interest, is the controversial ethnogenesis of an itinerant population of Ireland: the Travellers. The objectives of this study were: (1) to determine the genetic affinity of the Travellers to the general Irish population based on gene frequency data, subdivided by county, and (2) to explore the relationship between subpopulations of Ireland, given its turbulent history. The gene frequencies of standard genetic markers collected from populations residing in counties of Ireland and the Travellers were calculated and analysed using several multivariate methods. First, a relationship (R) matrix was used to ascertain the scaled variance covariance matrix of population similarity. Second, mean per locus heterozygosity (H) was regressed on distance of the region from the gene frequency centroid (r(ii)). The results of this study include: (1) the confirmation of Crawford's (1975, in Biosocial Interrelations in Population Adaptations, E. S. Watts et al. (eds), pp. 93-103) conclusions concerning the origins and genetic affinity of the Travellers; (2) based on several multivariate analyses, the major influence on population structure was unique historical events; and (3) Relethford and Crawford's (1995, American Journal of Physical Anthropology, 96, 25-38) hypothesis concerning the distinctiveness of the midland counties was verified by this study.     

Genetically hypertensive Brown Norway congenic rat strains suggest intermediate traits underlying genetic hypertension

Aim

To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background.

Methods

Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry in the single and combined congenics. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics.

Results

Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats demonstrated significantly lower baroreceptor sensitivity (β = -1.25 ± 0.17), whereas BN.GH2 (β = 0.66 ± 0.09) and BN.GH18 (β = 0.71 ± 0.07) had significantly decreased responses to ANGII from those observed in the BN (β = 0.88 ± 0.08).

Conclusion

The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.It is widely known that genetic factors play an important role in the onset and progression of hypertension and hypertension-induced end-organ damage in humans (1). As with all common multifactorial diseases, identifying the genetic components of hypertension in humans is complicated by allelic, locus, and epidemiological heterogeneity, as well as by a significant environmental component (2,3). Heritability measures for human essential hypertension range from 15-60% (4,5). Main approaches used to dissect genetics of hypertension include linkage analysis in families with hypertension, linkage studies in affected sib-pairs, and candidate gene and genome-wide association studies in candidate genes (6,7). However, with the exception of rare monogenic forms of hypertension such as Liddle’s syndrome (8), the syndrome of apparent mineralocorticoid excess (9), and glucocorticoid remediable aldosteronism (10), identification of the major genetic factors of essential hypertension remains elusive (11). In addition to genome-wide scans and association studies, the use of “intermediate” phenotypes is a relatively common tool proposed to help unravel the genetic basis of hypertension. Unfortunately, despite wide-spread discussion of using “intermediate” phenotypes (12,13), there is little hard evidence that they exist (14). Often what is thought to be an intermediate phenotype is in itself a complex trait (15,16).Several inbred hypertensive rat strains have been independently developed to mimic various aspects of the pathogenesis of human hypertension (17), with the expectation that the reduced heterogeneity in the rat will facilitate quantitative trait loci (QTL) and gene identification, which can then be followed-up in humans. In this study, we investigated the Genetically Hypertensive rat (GH/Omr). The GH rat was the first genetically inbred rat model for hypertension, characterized by early onset of hypertension (by the age of 6 weeks), hypercholesterolemia, cardiac hypertrophy, and vascular disease (18).Here we report the first complete genome linkage scan of hypertension and related traits in the GH rat and results of the initial physiological characterization of the single, double, and triple congenics, in comparison with the parental GH and BN strains.     

The genetic and environmental structure of fear and anxiety in juvenile twins

Fear and anxiety are conceptualized as responses to acute or potential threat, respectively. Adult twin studies found substantial interplay between genetic and environmental factors influencing fear disorders (phobias) and anxiety disorders. Research in children, however, has largely examined these factors independently. Thus, there exists a substantial knowledge gap regarding the underlying etiologic structure of these closely‐related constructs during development. Symptom counts for five fear (criticism, the unknown, death, animal, medical) and four anxiety (generalized, panic, separation, social) dimensions were obtained for 373 twin pairs ages 9–14. Multivariate twin modeling was performed to elucidate the genetic and environmental influences distributed amongst these dimensions. The best fitting model contained one genetic, two familial environmental, and two unique environmental factors shared between fear and anxiety symptoms plus dimension‐specific genetic and unique environmental factors. Although several environmental factors were shared between fear and anxiety dimensions, one latent factor accounted for genetic influences across both domains. While adult studies find somewhat distinct etiological differences between anxiety and phobic disorders, the current results suggest that their relative genetic and environmental influences are not as clearly demarcated in children. These etiological distinctions are more nuanced, likely contributing to the highly diffuse symptom patterns seen during development.     

Prepulse startle deficit in the Brown Norway rat: a potential genetic model

Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients. PPI was compared among 4 strains of rats: Sprague-Dawley, Spontaneously Hypertensive, Wistar Kyoto (WKY), and Brown Norway (BN). PPI was dramatically lower in BN versus the other strains, especially WKY, for both acoustic and airpuff startle stimuli, whereas startle amplitude was similar between BN and WKY. Female BN also had lower PPI than did female WKY. Response to increasing prepulse intensities showed a right shift in the BN relative to the WKY. Visual prepulses also showed deficiencies in BN versus WKY. The absence of background noise did not negate strain differences. Auditory brainstem response to clicks and tone pips revealed no differences in auditory threshold between the 2 strains. These results are the first to demonstrate that BN have impaired sensorimotor gating compared with WKY, without impaired acoustic acuity.     

Testing a genetic structure of blood-injury-injection fears

Multivariate genetic analyses were used to examine the genetic and environmental contributions to individual differences in fears of blood, injury, and injections in 659 twin pairs who completed questions concerning fear and fainting around blood, injury, and injections, and fainting in situations not involving blood, as well as the personality scales of Neuroticism, and Harm Avoidance. There was significant familial aggregation of blood fears but univariate analyses were unable to distinguish between additive genetic or shared environmental variables, or both, as the cause. The same was true of blood fainting. Non-blood-injury fainting was best explained by a model assuming shared and unique environmental variables. However, multivariate genetic analyses, which capitalise on extra information contained by all the covariance terms, indicated that the variance in blood-injury-injection fear was principally attributable to unique environmental events specific to this fear and additive genetic factors shared with fainting. The data are discussed in the context of models of blood-injury phobia that identify the need to consider separate etiological mechanisms for fear and fainting. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:377–384, 1998. © 1998 Wiley-Liss, Inc.     

Congenital dislocation of the hip joint in Norway V. Evaluation of genetic and environmental factors

The incidence of congenital dislocation of the hip joint (CDH) in Norway is high. Environmental factors and familial occurrence of CDH have been studied in 1147 probands with neonatal CDH and in 784 probands with late-diagnosis CDH. The proportion of affected sibs was 6 per cent in neonatal CDH and 8.5 per cent in late-diagnosis CDH. In 51 families, patients with neonatal CDH had sibs with late-diagnosis CDH, most of whom had been screened for CDH in the neonatal period. The distribution in families was computable with a polygenic mode of inheritance, and the heritability of CDH was calculated to be 74 per cent.
Breech presentation, the most important environmental factor, was observed in 15.7 per cent of the neonatal and in X.3 per cent of the late-diagnosis cases. A significant seasonal trend in month of birth was found in late-diagnosis CDH, with a maximum in early October. A higher percentage of birth rank one was found in CDH, but this was mostly due to an association between birth rank one and breech presentation. Probands with familial occurrence were significantly more often severely affected than those with no affected relatives. When several environmental factors were present in the history of a proband, the disorder tended to be more serious, and a familial occurrence of CDH was less likely. Concomitant anomalies were frequently found in CDH.     

脑结构形态学改变是精神分裂症的遗传内表型

目的 通过对首发精神分裂症患者及其未患病同胞的磁共振成像脑结构分析,探讨遗传因素对脑结构改变的影响程度,为发现精神分裂症的遗传内表型提供实验依据.方法 采用优化的基于体素的形态学研究方法对15例首发精神分裂症患者、19名首发精神分裂症患者未患病同胞及38名正常对照的大脑磁共振图像进行处理,采用一般线性模型进行统计分析.结果 与正常对照组相比,患者组在双侧颢叶、双侧枕叶、左侧岛叶、左侧额叶额上回及右豆状核苍白球灰质有明显减少;在双侧顶叶及双侧边缘叶扣带回灰质增加;未患病同胞组在右侧颞叶、双侧枕叶、左侧岛叶及左侧额叶中央前回等区域灰质明显减少;在左侧顶叶及双侧小脑后叶灰质增加.患者较同胞左侧顶叶楔前叶灰质有增加,未发现两者其他区域存在明显差异.结论 精神分裂症患者及其同胞存在相似的脑结构异常,遗传因素可能是导致精神分裂症脑结构异常的重要因素,提示脑结构形态学改变是精神分裂症的遗传内表型.     

Fine-scale human genetic structure in Western France

The difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendée Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses.     

The genetic structure of a tribal population, the Yanomama Indians. V. Comparisons of a series of genetic networks

The model of Cavalli-Sforza and Edwards was used to investigate the gentic relationships of thirty-seven Yanomama villages. Using gene frequency data from eleven genetic systems (MNS, P, Rh, Duffy, Kidd, Diego, Lewis, haptoglobin, Ge, PGM, and acid phosphatase), three hierarchical levels of analysis were carried out. The first level involved in the construction of a gentic network, based on genetic distance between villages, for each of three historically defined clusters of villages. Upon comparing the results with ethnohistory there was shown to be a good agreement between the historical development of a cluster and its genetic network. At the second level of analysis a genetic network was constructed in similar fashion for nineteen villages of the Western Yanomama subgroup, including the three village clusters previously analysed. At this level the integrity of the village clusters was largely maintaine, exceptions being due to specific socio-political events that resulted in changes of the composition of the village gene pool. The highest level resulted in the construction of a network for all thirty-seven villages which showed three of the five geographically defined tribal subgroups as distinct entities. The result of these analyses indicate that the model of Cavalli-Sforza and Edwards can under certain circimstances be used when the requirements of the midel arenot met, and furthermore that the rate of divergence of human populations may approach a steady state at the level of major tribal subgroupings.     

The genetic structure of English villages: surname diversity changes between 1976 and 1997

OBJECTIVE: To examine the change in the coefficient of relationship by isonymy (Ri) over a 21-year period. RESEARCH DESIGN: Ri was calculated from the surnames of males in the registers of electors for 15 villages near Oxford in 1976 and again in 1997. The within-residence component reflected the number of adult men of the same surname resident at the same address while the between-resident component of Ri was calculated by counting only one name of any surname at each address listed in the registers. RESULTS: Ri tended to decrease during the 21-year-period in 14 of the 15 villages and the between-resident component of Ri also tended to decrease in 14 of the villages. The within-residence component decreased in a statistically non-significant proportion (11 of the 15 villages). CONCLUSIONS: This study, in keeping with some but not all other surveys, showed that there was a tendency for random isonymy to decline in the 20th century. The reduction in the between-residence component can be accounted for by migration into the villages.     

The influence of clan structure on the genetic variation in a single Ghanaian village

Socioeconomic and cultural factors are thought to have an important role in influencing human population genetic structure. To explain such population structure differences, most studies analyse genetic differences among widely dispersed human populations. In contrast, we have studied the genetic structure of an ethnic group occupying a single village in north-eastern Ghana. We found a markedly skewed male population substructure because of an almost complete lack of male gene flow among Bimoba clans in this village. We also observed a deep male substructure within one of the clans in this village. Among all males, we observed only three Y-single-nucleotide polymorphism (SNP) haplogroups: E1b1a*-M2, E1b1a7a*-U174 and E1b1a8a*-U209, P277, P278. In contrast to the marked Y-chromosomal substructure, mitochondrial DNA HVS-1 sequence variation and autosomal short-tandem repeats variation patterns indicate high genetic diversities and a virtually random female-mediated gene flow among clans. On the extreme micro-geographical scale of this single Bimoba village, correspondence between the Y-chromosome lineages and clan membership could be due to the combined effects of the strict patrilocal and patrilineal structure. If translated to larger geographic scales, our results would imply that the extent of variation in uniparentally inherited genetic markers, which are typically associated with historical migration on a continental scale, could equally likely be the result of many small and different cumulative effects of social factors such as clan membership that act at a local scale. Such local scale effects should therefore be considered in genetic studies, especially those that use uniparental markers, before making inferences about human history at large.     

The genetic structure of English villages: surname diversity changes between 1976 and 1997

Objective: To examine the change in the coefficient of relationship by isonymy (R_i) over a 21-year period.

Research design: R_i was calculated from the surnames of males in the registers of electors for 15 villages near Oxford in 1976 and again in 1997. The within-residence component reflected the number of adult men of the same surname resident at the same address while the between-resident component of R_i was calculated by counting only one name of any surname at each address listed in the registers.

Results: R_i tended to decrease during the 21-year-period in 14 of the 15 villages and the between-resident component of R_i also tended to decrease in 14 of the villages. The within-residence component decreased in a statistically non-significant proportion (11 of the 15 villages).

Conclusions: This study, in keeping with some but not all other surveys, showed that there was a tendency for random isonymy to decline in the 20th century. The reduction in the between-residence component can be accounted for by migration into the villages.

Ziel: Untersuchung der Veränderung des Koeffizienten der Isonymiebeziehung (R_i) während einer Zeitdauer von 21 Jahren. Untersuchungsdesign: Anhand der Familiennamen von Männern aus den Wahlregistern von 15 Dörfern nahe Oxford wurde 1976 und nochmals 1997 der R_i berechnet. Die Intra-Wohnort-Komponente spiegelt die Anzahl der erwachsenen Männer mit gleichem Familiennamen wider, die am gleichen Wohnort wohnen, während die Inter-Wohnort-Komponente von R_i berechnet wurde durch die Zählung von nur einem Namen vom jeweiligen Familiennamen an jedem Wohnort, der in den Registern aufgeführt war. Ergebnisse: R_i zeigt eine Tendenz zur Verringerung in 14 der insgesamt 15 Dörfer während des Zeitraumes von 21 Jahren. In einem statistisch nicht signifikanten Anteil (11 von 15 Dörfern) nimmt die IntraWohnort-Komponente ab. Schlussfolgerungen: Die Studie zeigt in Übereinstimmung mit einigen, allerdings nicht allen anderen Erhebungen, dass es im 20. Jahrhundert eine Tendenz zur Abnahme zufälliger Isonymie gab. Die Verringerung der Inter-Wohnort-Komponente kann auf Migration in die Dörfer zurückgeführt werden.

Objectif: Examiner le changement du coefficient de consanguinité par isonymie (R_i) au cours d'une pé ode de 21 ans. Matériel et méthode: Le R_i a été calculé à partir des noms de famille de sujets masculins inscrits dans les registres d'électeurs de 15 villages proches d'Oxford, en 1976 puis à nouveau en 1997. Le composant intra-résidence reflète le nombre d'hommes adultes résidant à une même adresse alors que le composant inter-résidence a été calculé en comptant seulement un unique nom parmi tous ceux mentionnés à une même adresse. Résultats: Le R_i tend à décroître au cours de cette période de 21 ans dans 14 des 15 villages. Le composant intra-résidence a décru dans une proportion statistiquement non significative (11 des 15 villages). Conclusion: Cette étude montre comme d'autres, mais non pas toutes, qu'il y a une tendance à la décroissance de l'isonymie aléatoire au cours du 20^ème siècle. La réduction du composant entre résidences peut être expliquée par l'immigration dans les villages.