Hemochromatosis gene variants in three different ethnic populations: effects of admixture for screening programs

Genetic testing for hemochromatosis may have important implications for diagnosis and screening of the disease. However, the relative importance of mutations in the gene for hereditary hemochromatosis, HFE, may vary among populations, when the mutant allele frequencies and their penetrance in a particular genetic and environmental background are taken into account. We present data on the allele and genotype frequencies and population structure of two HFE genetic variants in three different ethnic groups from a highly mixed urban population (S?o Paulo, Brazil). Allele frequencies for both the C282Y and H63D HFE mutations showed significant differences among the studied populations (for the C282Y mutation, Euro-Brazilian 3.7%, admixed 0.7%, Afro-Brazilian 0.5%; and for the H63D mutation, Euro-Brazilian 20.3%, admixed 13.0%, Afro-Brazilian 6.4). The data substantiate a European origin for these mutations. Furthermore, they provide a basis for a more rational strategic planning of population screening programs for the disease.     

Genetic factors in iodine deficiency disorders: a general review

This review presents a summary of what is known about genetic factors possibly involved in iodine deficiency disorders. After an overview on thyroid iodine metabolism and the role of environmental factors in endemic goitre, we analyse genetic studies on endemic goitre reported in the literature. We hypothesize that endemic goitre is a multifactorial disease in which the major factor would be of environmental nature (iodine deficiency) with a lesser role for genetic factors. Mutations, in a heterozygote state, of one of the genes involved in tiered hormonogenesis could lead to a less effective metabolic pathway in the iodine transport or hormonogenesis. We also briefly review various hereditary disorders which may be involved in endemic goitre. Then, we postulate that the presence of some genetic variants in the population or the heterozygote status of individuals for thyroid hereditary disorders may influence the degree of the thyroid enlargement and/or hypothyroidism.     

Allelic variants of hereditary prions: The bimodularity principle

Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either “canonical” (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as “gene” and “allele” to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor.     

Linkage disequilibrium mapping in the Newfoundland population: a re-evaluation of the refinement of the Bardet–Biedl syndrome 1 critical interval

Genetically isolated populations, such as Newfoundland, have contributed greatly to the identification of disease-causing genes. A linkage disequilibrium (LD) study involving six Newfoundland families predicted a critical interval for Bardet-Biedl syndrome 1 (BBS1) (Young et al. in Am J Hum Genet 65:1680–1687, 1999), but the subsequent identification of BBS1 revealed that it lies outside this region. This suggested that either there is another gene responsible for BBS in these families or the Newfoundland population may not be ideal for LD studies. We screened these six Newfoundland families for mutations in BBS1 and found that affected individuals in five of them were homozygous for the same M390R mutation. There was no evidence for any BBS1 mutation in the affected individual in the sixth family. Therefore, one of the criteria for LD mapping was not met; namely, there should be a single disease-causing allele in the population. Haplotype analysis of unaffected individuals from south-west Newfoundland and English BBS1 patients homozygous for M390R, revealed that a second criterion for LD mapping was violated. The M390R mutation occurred in a common haplotype and both of these chromosomes, the ancestral wild-type and disease-causing haplotypes, were introduced to Newfoundland and spread by a founder effect. Moreover, it was found that disease-associated alleles occurred at relatively high frequencies in normal haplotypes and this probably accounted for the incorrect prediction in the previous LD study. Knowing the amount of genetic variation and its distribution in the Newfoundland population would be useful to maximize its potential for mapping hereditary disorders.     

Prevalence of hereditary pathologies in residents of the Kirov Province]

Medical-genetic study was carried out in the population of Kirov Province (population size about 120.000). 203 families with 334 affected with hereditary disorders were registered. The correctness of pathology classification for the inheritance type was confirmed by segregational analysis. The load of hereditary diseases in the population was: 1.25 +/- 0.06 for autosomal dominant, 1.37 +/- 0.07 for autosomal recessive and 0.22 +/- 0.06 for X-linked recessive disorders. It is suggested that variability in the values of the load of autosomal recessive disorders is determined to the large extent by genetic structure of the population.     

Medical genetic study of the population of Turkmenia. III. Hereditary pathology in Turkmen Nokhurlis

Medical-genetic investigations were carried out in isolated population of Nokhurlis inhabiting some villages of Ashkhabad and Krasnovodsk provinces. A high coefficient of inbreeding, high endogamy, and low coefficients of migration were found for this population. Two hereditary disorders are relatively frequent among the Nokhurlis and lacking in neighboring populations. The frequency of the autosomal dominant gene for congenital cataract is 0.26% and that of the autosomal recessive gene for a peculiar form of obesity is 2.47%. In both cases, the main factor affecting gene accumulation appears to be the result of genetical drift effect. The total load of hereditary diseases of higher in Nokhurlis than in other Turkmen populations. The connection between the population structure of Nokhurlis and the accumulation of hereditary disorders is discussed.     

No incidence of DUMPS carriers in Polish dairy cattle

DUMPS (Deficiency of Uridine Monophosphate Synthase) is a hereditary recessive disorder in Holstein cattle causing early embryo mortality during its implantation in the uterus. The only way to avoid the economic losses is early detection of DUMPS carriers. Because American Holstein semen has been intensively imported to Poland since 1970, there was a risk that DUMPS could have spread in Polish dairy cattle. In our study, 2209 dairy cattle of the Polish Holstein breed have been screened by the DNA test. The dominant group was young bulls entering the testing program (1171) and proven bulls (781). They represented all sires entering Polish breeding programs between 1999 and 2003. Also, 257 sire dams were included in the screening program. No DUMPS carrier has been found. Our results then indicate that the population of dairy cattle reared in Poland is free from DUMPS. Because of the economical significance of the DUMPS mutation and its recessive mode of inheritance, attention has to be paid to any case of a bull having in his origin any known DUMPS carrier. Such a bull should be tested and if positive eliminated from the active population. Also, young bulls (testing bulls) should be screened for DUMPS if in their progeny a high incidence of embryo mortality is observed and their genealogy cannot exclude their relatedness to any DUMPS carriers.     

Normal iron metabolism and the pathophysiology of iron overload disorders

Iron overload disorders represent a heterogenous group of conditions resulting from inherited and acquired causes. If undiagnosed they can be progressive and fatal. Early detection and phlebotomy prior to the onset of cirrhosis can reduce morbidity and normalise life expectancy. We now have greater insight into the complex mechanisms of normal and disordered iron homeostasis following the discovery of new proteins and genetic defects. Here we review the normal mechanisms and regulation of gastrointestinal iron absorption and liver iron transport and their dysregulation in iron overload states. Advances in the understanding of the natural history of iron overload disorders and new methods for clinical detection and management of hereditary haemochromatosis are also reviewed. The current screening strategies target high-risk groups such as first-degree relatives of affected individuals and those with clinical features suggestive of iron loading. Potential ethical, legal and psychosocial issues arising through application of genetic screening programs need to be resolved prior to implementation of general population screening programs.     

Hemochromatosis and the enigma of misplaced iron: Implications for infectious disease and survival

The mystery surrounding the apparent lack of iron within the macrophages of individuals with hereditary hemochromatosis, a condition of excessive uptake of dietary iron, has yet to be fully explained. We have suggested that iron deficiency of macrophages in people with hereditary hemochromatosis mutations is associated with increased resistance to infection by Yersinia and other intracellular pathogens, a selection pressure resulting in unusually high current population frequencies of hereditary hemochromatosis mutations. Such selection pressure has been called Epidemic Pathogenic Selection (EPS). In support of the theory of EPS, a considerable number of virulent species of bacteria multiply mainly in iron-rich macrophages of their mammalian hosts. Among these fastidious pathogens are strains of Chlamydia, Coxiella, Francisella, Legionella, Mycobacterium, Salmonella and Yersinia. Iron deficiency of macrophages of persons with hereditary hemochromatosis gene mutations may result in increased resistance to members of these bacterial pathogens. People with genes that result in hereditary hemochromatosis may be protected against coronary artery disease associated with Chlamydia and Coxiella infection in the absence of iron overload. In the clinical setting, when a patient appears to be iron deficient, the reason for this should be carefully evaluated. Iron supplementation may adversely affect the health of individuals who have mounted an acute phase response to infection, injury or stress, or who carry genes predisposing them to iron overload disorders.     

Elements of an occupational health and safety program: deficiencies identified by AAALAC international

An effective occupational health and safety program is critical to ensure personnel safety in working with animals. The authors present data compiled from AAALAC international site visits conducted between 1993 and 1999, which indicate how programs can fall short of current recommendations.     

Effect of a major gene in inheritance of the cortisol level in the peripheral blood of a domesticable population of foxes (Vulpes vulpes)]

Domestication of animals is known to be associated with hereditary changes in the pituitary-adrenal system which regulates most important stages of ontogenesis. Cortisol is one of the basic indices of activity of this system. A segregation analysis of inheritance of cortisol content in blood of domestic silver fox population was undertaken. The results of the analysis point to an effect of a major gene controlling this quantitative trait, and indicate that breeding for domestic behaviour is accompanied by selection of individuals homozygous with respect to recessive genes controlling the cortisol level.     

Simultaneous estimation of mixing rates and genetic drift under successive sampling of genetic markers with application to the mud crab (Scylla paramamosain) in Japan

In stock enhancement programs, it is important to assess mixing rates of released individuals in stocks. For this purpose, genetic stock identification has been applied. The allele frequencies in a composite population are expressed as a mixture of the allele frequencies in the natural and released populations. The estimation of mixing rates is possible, under successive sampling from the composite population, on the basis of temporal changes in allele frequencies. The allele frequencies in the natural population may be estimated from those of the composite population in the preceding year. However, it should be noted that these frequencies can vary between generations due to genetic drift. In this article, we develop a new method for simultaneous estimation of mixing rates and genetic drift in a stock enhancement program. Numerical simulation shows that our procedure estimates the mixing rate with little bias. Although the genetic drift is underestimated when the amount of information is small, reduction of the bias is possible by analyzing multiple unlinked loci. The method was applied to real data on mud crab stocking, and the result showed a yearly variation in the mixing rate.     

Attitudes toward genetic testing among the general population and relatives of patients with a severe genetic disease: a survey from Finland.

In the present study we explore the attitudes of the Finnish population toward genetic testing by conducting a questionnaire study of a stratified sample of the population as well as of family members of patients with a severe hereditary disease, aspartylglucosaminuria (AGU). The questionnaire evaluated attitudes toward gene tests in general and also respondents' preparedness to undergo gene tests for predictive testing, carrier detection, prenatal diagnosis, and selective abortion, in theoretical situations. The results of the study indicate that both the Finnish population in general and family members of AGU patients have a favorable attitude toward genetic testing. However, a commonly expressed reason against testing was that test results might lead to discrimination in employment or insurance policies. Based on the responses, we predict that future genetic testing programs will most probably be met with a high acceptance rate by the Finnish population.     

Red blood cell membrane defects

We present an overview of the currently known molecular basis of red cell membrane disorders. A detailed discussion of the structure of the red cell membrane and the pathophysiology and clinical aspects of its disorders is reported. Generally speaking, hereditary spherocytosis (HS) results from a loss of erythrocyte surface area. The mutations of most cases of HS are located in the following genes: ANK1, SPTB, SLC4A1, EPB42 and SPTA1, which encode for ankyrin, spectrin beta-chain, the anion exchanger 1 (band 3), protein 4.2 and spectrin alpha-chain, respectively. Hereditary elliptocytosis (HE) reflects a diminished elasticity of the skeleton. Its aggravated form, hereditary pyropoikilocytosis (HPP), implies that the skeleton undergoes further destabilization. The mutations responsible for HE and HPP, lie in the SPTA1 and SPTB gene, and in the EPB41 gene encoding protein 4.1. Allele alpha LELY is a common polymorphic allele, which plays the role of an aggravating factor when it occurs in trans of an elliptocytogenic allele of the SPTA1 gene. Southeast Asian ovalocytosis derives from a change in band 3. The genetic disorders of membrane permeability to monovalent cations required a positional cloning approach. In this respect, channelopathies represent a new frontier in the field. Dehydrated hereditary stomatocytosis (DHS) was shown to belong to a pleiotropic syndrome: DHS + fetal edema + pseudohyperkalemia, which maps 16q23-24. Splenectomy is strictly contraindicated in DHS and another disease of the same class, overhydrated hereditary stomatocytosis, because it increases the risk of thromboembolic accidents.     

Do tribal communities show an inverse relationship between sickle cell disorders and glucose-6-phosphate dehydrogenase deficiency in malaria endemic areas of Central-Eastern India?

Tribal communities in India constitute the largest tribal population in the world. There are about 635 biological isolates (tribes and subtribes), which constituted 8.08% (about 84.3 million) of the total population of India as per the 2001 census. Out of 635 scheduled tribes (aborigines), 62 live in the state of Orissa alone forming about 10.8% of the tribal population of India. Orissa state occupies an important place, being the 3rd in rank for the highest concentration of tribal population in the country. In India, tribal communities are highly vulnerable to hereditary diseases and have a high degree of malnutrition, morbidity and mortality. The sickle cell haemoglobinopathy and glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency are important genetic and public health problems in Central-Eastern part of India. In order to map out these genetic disorders among the tribal people, a cross-section of 15 major tribal communities from different parts of Orissa was randomly screened for haemoglobin variants and G6PD deficiency. The high frequency of sickle cell haemoglobinopathy (0-22.4%) and G6PD deficiency (4.3-17.4%), with beta-thalassemia trait (0-8.5%) taking almost an intermediate position, was observed. For G6PD deficiency, hemizygous males as well as female heterozygotes and female homozygotes were detected. Twelve cases showed compound heterozygosity for sickle cell haemoglobinopathy and G6PD deficiency. There seems to be a trend towards an inverse relationship between the sickle cell allele and G6PD deficiency, and sickle cell and beta-thalassemia allele in a cross-section of malaria endemic (Plasmodium falciparum) tribal communities in Orissa. When the frequency of sickle cell allele decreases in a cross-section of malaria endemic tribal population, the frequency of G6PD enzyme deficiency and beta-thalassemia allele increases and vice versa. Natural selection had played a major role in favour of sickle cell, beta-thalassemia and G6PD mutation alleles so that they had probably evolved as a protective mechanism against the lethal effects of malaria in this part of the country. However, the calculated values of 0.074, 0.218 and 0.337, respectively, of Pearson's correlation co-efficient (r), showed no correlation between sickle cell disorders and G6PD deficiency, sickle cell disorders and beta-thalassemia, and G6PD deficiency and beta-thalassemia.     

Monitoring and management of the endangered Cape mountain zebra Equus zebra zebra in the Western Cape, South Africa

De Hoop Nature Reserve and a neighbouring conservancy contain the most genetically diverse subpopulation of the Endangered (IUCN) Cape mountain zebra ( Equus zebra zebra Linnaeus 1758). Although vital for the long-term stability of the meta-population, the population had received limited monitoring post-1999. We summarize data obtained during a population monitoring programme established in 2005. Ninety-nine individuals were identified indicating a decline in annual population growth from 6.6% (1995–1999) to 4.5% (1999–2005). The population was male biased and the deficit of females is likely to have prevented additional breeding herd formation resulting in excess nonbreeding males. These animals are currently of limited reproductive value to the meta-population and may be contributing to the decline in reproductive potential at De Hoop by competing for limited resources. One solution may be to translocate 'excess' males to reinforce existing small populations or establish new populations with females from elsewhere provided that a minimum of 78 animals is maintained at De Hoop to limit genetic loss. Population monitoring and effective management strategies for the De Hoop population and the meta-population are vital to ensure the long-term survival of Cape mountain zebra and for the success of other species recovery programmes.     

心脏发育过程中的信号调控机制研究

我国是出生缺陷高发国家,其中先天性心脏病在各类出生缺陷中居于首位,严重地影响我国的人口素质.同样,后天性心脏血管疾病（心血管疾病）也是影响国民健康和社会发展的主要疾病.近年来研究表明,所谓＂后天性＂心脏血管疾病虽然大多不在胚胎期表现出功能异常,但遗传因素在发病过程中也起关键作用,因此,＂后天性＂心血管疾病也有其发育生物学基础.在一些心血管疾病中,胚胎发育基因如ANF和β-MHC的表达说明胚胎发育的某些机制参与了发病过程.由于出生缺陷和心血管疾病的防治是我国公共卫生和社会发展中亟待解决的重大健康问题,了解心血管系统正常发生发育规律和机制及发病机理并在此基础上建立新的防治策略和防治措施是生命科学需要解决的重大基础科学问题.本文主要综述了目前模式动物,特别是小鼠心脏发育过程中的信号传导调控机制的研究现状及进展.     

Genome-wide analysis in endangered populations: a case study in Barbaresca sheep

Analysis of genomic data is becoming increasingly common in the livestock industry and the findings have been an invaluable resource for effective management of breeding programs in small and endangered populations. In this paper, with the goal of highlighting the potential of genomic analysis for small and endangered populations, genome-wide levels of linkage disequilibrium, measured as the squared correlation coefficient of allele frequencies at a pair of loci, effective population size, runs of homozygosity (ROH) and genetic diversity parameters, were estimated in Barbaresca sheep using Illumina OvineSNP50K array data. Moreover, the breed’s genetic structure and its relationship with other breeds were investigated. Levels of pairwise linkage disequilibrium decreased with increasing distance between single nucleotide polymorphisms. An average correlation coefficient <0.25 was found for markers located up to 50 kb apart. Therefore, these results support the need to use denser single nucleotide polymorphism panels for high power association mapping and genomic selection efficiency in future breeding programs. The estimate of past effective population size ranged from 747 animals 250 generations ago to 28 animals five generations ago, whereas the contemporary effective population size was 25 animals. A total of 637 ROH were identified, most of which were short (67%) and ranged from 1 to 10 Mb. The genetic analyses revealed that the Barbaresca breed tended to display lower variability than other Sicilian breeds. Recent inbreeding was evident, according to the ROH analysis. All the investigated parameters showed a comparatively narrow genetic base and indicated an endangered status for Barbaresca. Multidimensional scaling, model-based clustering, measurement of population differentiation, neighbor networks and haplotype sharing distinguished Barbaresca from other breeds, showed a low level of admixture with the other breeds considered in this study, and indicated clear genetic differences compared with other breeds. Attention should be given to the conservation of Barbaresca due to its critical conservation status. In this context, genomic information may have a crucial role in management of small and endangered populations.     

Quantitative DNA pooling to increase the efficiency of linkage analysis in autosomal dominant disease

DNA pooling is an efficient method to rapidly perform genome-wide linkage scans in autosomal recessive diseases in inbred populations where affected individuals are likely to be homozygous for alleles near the disease gene locus. We wanted to examine whether this approach would detect linkage in autosomal dominant (AD) disorders where affected individuals may share one allele identical by descent at loci tightly linked to the disease. Two large outbred pedigrees in which the AD diseases familial venous malformation (FVM) and hereditary hemorrhagic telangiectasia (HHT1), linked to 9p and 9q, respectively, were investigated. Separate pools of DNA from affected (n = 21 for FVM and 17 for HHT1) and unaffected family members (n = 9 FVM and HHT1), and 25 unrelated population controls were established. Polymorphic markers spanning chromosome 9 at approximately 13.5-cM intervals were amplified using standard PCR. Allele quantitation was performed with a fluorimager. Visual inspection of allele intensities and frequency distributions suggested a shift in frequency of the most common allele in the affecteds lane when compared to control lanes for markers within 30 cM of the FVM and HHT1 loci. These subjective assessments were confirmed statistically by testing for the difference between two proportions (one-sided; P≤ 0.05). When using population controls, the true-positive rates for FVM and HHT1 were 5/5 and 2/5 markers, respectively. False-positive rates for FVM and HHT1 were 3/9 and 2/9, respectively. In both AD diseases investigated, quantitative DNA pooling detected shifts in allele frequency, thus identifying areas of known linkage in most cases. The utility of this technique depends on the size of the pedigree, frequency of the disease-associated allele in the population, and the choice of appropriate controls. Although the false-positive rate appears to be high, this approach still serves to reduce the amount of overall genotyping by about 60%. DNA pooling merits further investigation as a potential strategy in increasing the efficiency of genomic linkage scans. Received: 12 May 1997 / Accepted: 29 October 1997