Showing papers in "Annals of Human Genetics in 2007"

Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms.

Abstract: Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level. A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour, but only limited genetic evidence for positive selection has been presented. To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset, studying single nucleotide polymorphisms (SNPs), and analyzed 55 genes in detail. We identified eight genes that are associated with the melanin pathway (SLC45A2, OCA2, TYRP1, DCT, KITLG, EGFR, DRD2 and PPARD) and presented significant differences in genetic variation between Europeans, Africans and Asians. In six of these genes we detected, by means of the EHH test, variability patterns that are compatible with the hypothesis of local positive selection in Europeans (OCA2, TYRP1 and KITLG) and in Asians (OCA2, DCT, KITLG, EGFR and DRD2), whereas signals were scarce in Africans (DCT, EGFR and DRD2). Furthermore, a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed. Overall, our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians, whereas dark skin color seems of unique origin, reflecting the ancestral state in humans.

On the nonexistence of adaptive topographies

Abstract: Consider a population of individuals whose fitnesses are dependent on a single locus at which there are lc alleles, A,, ..., A,, with frequencies p l , ...,p, (Xp, = 1). The fitness of an individual, Ai A,, is denoted by w,, ( = wji) and is such that the wij are non-negative constants proportional to the contributions which newly formed zygotes of the form Ai A, make to the gametes which form the next generation. Consider a generation which is the result of random mating, and in which the allele frequencies are p,, . . . , pk. Then the frequency of the zygotes A, A, is p: and the frequency of zygotes such as A, A, (or A, A,) is 2p,p, if i + j . For the latter it is convenient to make a distinction between A, A, and A, A, by supposing that the Ai is derived from the father in the first and from the mother in the second. The frequency of each is pip,. Then the 'mean fitness' of the population is

The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset.

Abstract: Age of onset for Huntington's disease (HD) varies inversely with the length of the disease-causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R-squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two-segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log-transformed age of onset against CAG repeat length reveals this segmental relationship. This two-segment exponential regression on age of onset data increases the adjusted R-squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two-segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) = 11.13, P= 2 x 10(-5)] and in the HD MAPS cohort [F(2, 688) = 38.27, P= 2 x 10(-16)]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult-onset range of CAG repeats than in the juvenile-onset range.

Cytogenetic studies in leucocytes on the general population: subjects of ages 65 years and more.

Abstract: No results have yet been published of cytogenetic studies on a random sample of the general population. Such studies, however, are desirable for a number of reasons. First, Jacobs, Court Brown & Doll (1961), Jacobs et al. (1963) have reported finding an increase in the number of aneuploid cells with age in blood cultures from apparently normal individuals. These studies were made on a non-randomly selected group of individuals, and it is desirable to see whether the same effect is present in a randomly chosen group of subjects. Secondly, it is usual for small numbers of cells in blood cultures from normal individuals to contain structural abnormalities of the chromatid or chromosome type. It is known that the proportion of cells with chromosomal abnormalities can be markedly increased in blood cultures following exposure in wiwo to high doses of radiation (Tough, Buckton, Baikie & Court Brown, 1961 ; Bender & Gooch, 1962, 1963 ; Buckton, Jacobs, Court Brown & Doll, 1962). In theory it may be anticipated that some increase will follow exposure to low doses, and the search for such an effect will be helped by knowledge of the frequency of cells with structural abnormdities in a sample of the general population. Thirdly, it has for some time been known that, occasionally, variations occur in the morphology of the acrocentric chromosomes and chromosome no. 16, and it is of interest to determine the frequency of these phenomena (Sasaki, Makino & Kajii, 1963; Chandra & Hungerford, 1963; Chapelle, Aula & Kivalo, 1963). Finally, there have been a number of reports tending to associate apparently minor chromosomal abnormalities with pathological states (Tough et al. 1962; Gunz, Fitzgerald & Adams, 1962; Schmid, 1962). Some of these reported associations, however, may be fortuitous, and an important aid to determining whether this is so will be the study of the frequency of minor abnormalities and variations in the general population. This communication reports the results of the study of 189 elderly subjects who were randomly chosen from the general population, and for whom leucocyte cultures have been examined. Particular emphasis has been laid on three kinds of investigation, the distribution of chromosome counts, the frequency of cells with chromatid and chromosome structural abnormalities, and the frequency of subjects with abnormalities or with well-marked variations of the karyotype in all their cells. MATERIAL AND METHODS During 1961 and 1962 the staff of the Edinburgh Geriatric Hospital Service studied the medical status and social welfare of a random sample of subjects of ages 65 years and more drawn from the lists of three general practices. One was a rural practice outside Edinburgh and two were urban practices within Edinburgh. The opportunity was taken to undertake chromosome

Admixture and Population Stratification in African Caribbean Populations

Abstract: Throughout biomedical research, there is growing interest in the use of ancestry informative markers (AIMs) to deconstruct racial categories into useful variables. Studies on recently admixed populations have shown significant population substructure due to differences in individual ancestry; however, few studies have examined Caribbean populations. Here we used a panel of 28 AIMs to examine the genetic ancestry of 298 individuals of African descent from the Caribbean islands of Jamaica, St. Thomas and Barbados. Differences in global admixture were observed, with Barbados having the highest level of West African ancestry (89.6%+/- 2.0) and the lowest levels of European (10.2%+/- 2.2) and Native American ancestry (0.2%+/- 2.0), while Jamaica possessed the highest levels of European (12.4%+/- 3.5) and Native American ancestry (3.2%+/- 3.1). St. Thomas, USVI had ancestry levels quite similar to African Americans in continental U.S. (86.8%+/- 2.2 West African, 10.6%+/- 2.3 European, and 2.6%+/- 2.1 Native American). Significant substructure was observed in the islands of Jamaica and St. Thomas but not Barbados (K=1), indicating that differences in population substructure exist across these three Caribbean islands. These differences likely stem from diverse colonial and historical experiences, and subsequent evolutionary processes. Most importantly, these differences may have significant ramifications for case-control studies of complex disease in Caribbean populations.

Identification and analysis of genomic regions with large between-population differentiation in humans

Abstract: Summary The primary aim of genetic association and linkage studies is to identify genetic variants that contribute to phenotypic variation within human populations. Since the overwhelming majority of human genetic variation is found within populations, these methods are expected to be effective and can likely be extrapolated from one human population to another. However, they may lack power in detecting the genetic variants that contribute to phenotypes that differ greatly between human populations. Phenotypes that show large differences between populations are expected to be associated with genomic regions exhibiting large allele frequency differences between populations. Thus, from genome-wide polymorphism data genomic regions with large allele frequency differences between populations can be identified, and evaluated as candidates for large between-population phenotypic differences. Here we use allele frequency data from ∼1.5 million SNPs from three human populations, and present an algorithm that identifies genomic regions containing SNPs with extreme Fst. We demonstrate that our candidate regions have reduced heterozygosity in Europeans and Chinese relative to African-Americans, and are likely enriched with genes that have experienced positive natural selection. We identify genes that are likely responsible for phenotypes known to differ dramatically between human populations and present several candidates worthy of future investigation. Our list of high Fst genomic regions is a first step in identifying the genetic variants that contribute to large phenotypic differences between populations, many of which have likely experienced positive natural selection. Our approach based on between population differences can compliment traditional within population linkage and association studies to uncover novel genotype-phenotype relationships.

Association of a common interferon regulatory factor 5 (IRF5) variant with increased risk of systemic lupus erythematosus (SLE).

Abstract: Interferon regulatory factor 5 (IRF5) belongs to a family of transcription factors that control the transactivation of type I interferon system-related genes, as well as the expression of several other genes involved in immune response, cell signalling, cell cycle control and apoptosis. Two recent studies reported a significant association between the IRF5/rs2004640 T allele and systemic lupus erythematosus (SLE). The purpose of this study was to determine whether the reported rs2004640 T allele association could be replicated in our independent SLE case-control sample. We genotyped DNA samples from 370 white SLE-affected female subjects and 462 white healthy female controls using the TaqMan Assay-on-Demand for rs2004640, and performed a case-control genetic association analysis. Frequency of the rs2004640 T allele was significantly higher in cases than in controls (56.5% vs. 50%; P= 0.008). The odds ratio for T allele carriers was 1.68 (95% CI: 1.20 - 2.34; P= 0.003). Our results in an independent case-control sample confirm the robust association of the IRF5/rs2004640 T allele with SLE risk, and further support the relevance of the type I interferon system in the pathogenesis of SLE and autoimmunity.

A Bidirectional Corridor in the Sahel‐Sudan Belt and the Distinctive Features of the Chad Basin Populations: A History Revealed by the Mitochondrial DNA Genome

Abstract: The Chad Basin was sparsely inhabited during the Stone Age, and its continual settlement began with the Holocene. The role played by Lake Chad in the history and migration patterns of Africa is still unclear. We studied the mitochondrial DNA (mtDNA) variability in 448 individuals from 12 ethnically and/or economically (agricultural/pastoral) different populations from Cameroon, Chad, Niger and Nigeria. The data indicate the importance of this region as a corridor connecting East and West Africa; however, this bidirectional flow of people in the Sahel-Sudan Belt did not erase features peculiar to the original Chad Basin populations. A new sub-clade, L3f2, is described, which together with L3e5 is most probably autochthonous in the Chad Basin. The phylogeography of these two sub-haplogroups seems to indicate prehistoric expansion events in the Chad Basin around 28,950 and 11,400 Y.B.P., respectively. The distribution of L3f2 is virtually restricted to the Chad Basin alone, and in particular to Chadic speaking populations, while L3e5 shows evidence for diffusion into North Africa at about 7,100 Y.B.P. The absence of L3f2 and L3e5 in African-Americans, and the limited number of L-haplotypes shared between the Chad Basin populations and African-Americans, indicate the low contribution of the Chad region to the Atlantic slave trade.

No association of the ACTN3 gene R577X polymorphism with endurance performance in Ironman Triathlons.

Abstract: Summary Alpha-actinins are major structural components of the Z-discs in skeletal muscle. Alpha-actinin 3 is encoded by the ACTN3 gene and is expressed only in type II muscle fibres. Homozygosity for the nonsense mutation, 577X, within ACTN3 results in deficiency of α-actinin-3 but does not result in an abnormal muscular phenotype. Previous research has found an association of the 577R allele with sprinting and/or power performance. It has also been suggested that the 577X allele may confer an advantage during endurance events. Four hundred and fifty seven Caucasian male triathletes who completed either the 2000 and/or 2001 226 km South African Ironman Triathlons, and 143 Caucasian controls, were genotyped for the R577X mutation within the ACTN3 gene. There were no significant differences in either the genotype (P = 0.486) or allele (P = 0.375) frequencies within the fastest, middle of the field or slowest Caucasian male finishers and the control population. In conclusion, the R577X polymorphism within the ACTN3 gene was not associated with ultra-endurance performance in the 2000 and 2001 South African Ironman Triathlons.

Common adiponectin gene variants show different effects on risk of cardiovascular disease and type 2 diabetes in European subjects.

Abstract: Summary Alterations in the secretion of adipokines may explain the link between obesity, type 2 diabetes (T2DM) and coronary artery disease (CAD). These conditions have been associated with variation in the adiponectin gene, although evidence for this relationship has been variable, with differences found even in similar samples. This study aims to clarify these inconsistencies by determining the impact of identified adiponectin gene (ADIPOQ) variants (− 11391G>A,− 1377C>G[promoter] and +45T>G[exon 2] and +276G>T[intron 2]) on the prospective risk of CAD and T2DM in healthy men, and on adverse metabolic markers, in myocardial infarct survivors and controls from different parts of Europe. The hazard ratio for cardiovascular disease varied across the − 11391GG/GA/AA(p = 0.03) and − 11371CC/CG/GG(p = 0.05) genotypes only. In contrast, only the +45T>G variant (3.80[1.76-8.24]) was associated with T2DM, while two haplotypes GCTT/GCGG (p T(p = 0.01) increased risk in interaction with obesity. The variants were associated with a number of biomarkers in Southern but not Northern Europe (p = 0.01), despite no significant differences in allele or haplotype frequencies (p > 0.44). A risk haplotype could not be identified in either sample. Adiponectin gene variants are hence currently poor markers for the development of T2DM and CAD. Their influence on risk depends significantly on interactions that are not currently understood with either genetic variation elsewhere or the environment of the sample studied.

Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.

Abstract: Summary We analyzed 1,954 Spanish cystic fibrosis (CF) alleles in order to define the molecular spectrum of mutations in the CFTR gene in Spanish CF patients. Commercial panels showed a limited detection power, leading to the identification of only 76% of alleles. Two scanning techniques, denaturing gradient gel electrophoresis (DGGE) and single strand conformation polymorphism/hetroduplex (SSCP/HD), were carried out to detect CFTR sequence changes. In addition, intragenic markers IVS8CA, IVS8-6(T)n and IVS17bTA were also analyzed. Twelve mutations showed frequencies above 1%, p.F508del being the most frequent mutation (51%). We found that eighteen mutations need to be studied to achieve a detection level of 80%. Fifty-one mutations (42%) were observed once. In total, 121 disease-causing mutations were identified, accounting for 96% (1,877 out of 1,954) of CF alleles. Specific geographic distributions for the most common mutations, p.F508del, p.G542X, c.1811 + 1.6kbA > G and c.1609delCA, were confirmed. Furthermore, two other relatively common mutations (p.V232D and c.2789 + 5G > A) showed uneven geographic distributions. This updated information on the spectrum of CF mutations in Spain will be useful for improving genetic testing, as well as to facilitate counselling in people of Spanish ancestry. In addition, this study contributes to defining the molecular spectrum of CF in Europe, and corroborates the high molecular mutation heterogeneity of Mediterranean populations.

The birth prevalence of PKU in populations of European, South Asian and sub-Saharan African ancestry living in South East England.

Abstract: Summary Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism (OMIM 261600). Treatment with a low-phenylalanine diet following early ascertainment by newborn screening prevents impaired cognitive development, themajor disease phenotype in PKU. The overall birth prevalence of PKU in European, Chinese and Korean populations is ∼ 1/10,000. Since the human PAH locus contains PKU-causing alleles and polymorphic core haplotypes that describeand corroborate an out-of-Africa range expansion in modern human populations, it is of interest to know the prevalenceof PKU in different ethnic groups with diverse geographical origin. We estimated PKU prevalence in South East England,where a sizeable proportion of the population are of Sub-Saharan African or South Asian ancestry. Over the period 1994to 2004 167 children were diagnosed with PKU. Using birth registration and census data to derive denominators, PKUbirth prevalence per 10,000 live births (95% Bayesian credible intervals) was estimated to be 1.14 (0.96–1.33) amongwhite, 0.11 (0.02–0.37) among black, and 0.29 (0.10–0.63) among Asian ethnic groups. This suggests that PKU is upto an order of magnitude less prevalent in populations with Sub-Saharan African and South Asian ancestry that havemigrated to the UK.Keywords: phenylketonuria, prevalence, ethnic groups

Ethnic differences in interleukin 6 (IL-6) and IL6 receptor genes in spontaneous preterm birth and effects on amniotic fluid protein levels.

Abstract: Summary Preterm birth (PTB) is a significant neonatal health problem that is more common in African-Americans (AA) than in European-Americans (EA). Part of this disparity is likely to result from the differing genetic architectures of EA and AA. To begin assessing the role of these differences, patterns of genetic variation in two previously proposed candidate genes, encoding interleukin 6 (IL6) and its receptor (IL6R), were analyzed in mothers and fetuses from 496 EA birth-events (149 cases and 347 controls) and 397 birth-events in AA (76 cases and 321 controls). IL-6 levels in amniotic fluid (AF) samples were determined in a subset of these pregnancies. Case-control comparisons revealed a single SNP in IL6R associated with PTB (p=0.04 for allelic and p=0.05 for genotype association). In addition, all of the SNPs studied showed significant frequency differences between AA and EA in at least one comparison, significantly in excess of that expected from general population databases. Higher IL-6 concentrations were associated with the IL6 SNP -661 in EA preterm samples (p=0.0056), and this result seems to be driven by microbial invasion of the amniotic cavity, indicating a gene by infection interaction. These findings indicate that, as a function of IL6 genotype, EA and AA women respond differently to infection with respect to their expression of IL-6. Our data support differential genetic control of levels of IL-6 in amniotic fluid between EA and AA.

Deconstructing Jaco: genetic heritage of an Afrikaner.

Abstract: Summary It is often assumed that Afrikaners stem from a small number of Dutch immigrants. As a result they should be genetically homogeneous, show founder effects and be rather inbred. By disentangling my own South African pedigree, that is on average 12 generations deep, I try to quantify the genetic heritage of an Afrikaner. As much as 6% of my genes have been contributed by slaves from Africa, Madagascar and India, and a woman from China. This figure compares well to other genetic and genealogical estimates. Seventy three percent of my lineages coalesce into common founders, and I am related in excess of 10 times to 20 founder ancestors (30 times to Willem Schalk van der Merwe). Significant founder effects are thus possible. The overrepresentation of certain founder ancestors is in part explained by the fact that they had more children. This is remarkable given that they lived more than 300 years (or 12 generations) ago. DECONSTRUCT, a new program for pedigree analysis, identified 125 common ancestors in my pedigree. However, these common ancestors are so distant from myself, paths of between 16 and 25 steps in length, that my inbreeding coefficient is not unusually high (f ≈ 0.0019).

Multivariate Linkage Analysis of Specific Language Impairment (SLI)

Abstract: Specific language impairment (SLI) is defined as an inability to develop appropriate language skills without explanatory medical conditions, low intelligence or lack of opportunity. Previously, a genome scan of 98 families affected by SLI was completed by the SLI Consortium, resulting in the identification of two quantitative trait loci (QTL) on chromosomes 16q (SLI1) and 19q (SLI2). This was followed by a replication of both regions in an additional 86 families. Both these studies applied linkage methods to one phenotypic trait at a time. However, investigations have suggested that simultaneous analysis of several traits may offer more power. The current study therefore applied a multivariate variance-components approach to the SLI Consortium dataset using additional phenotypic data. A multivariate genome scan was completed and supported the importance of the SLI1 and SLI2 loci, whilst highlighting a possible novel QTL on chromosome 10. Further investigation implied that the effect of SLI1 on non-word repetition was equally as strong on reading and spelling phenotypes. In contrast, SLI2 appeared to have influences on a selection of expressive and receptive language phenotypes in addition to non-word repetition, but did not show linkage to literacy phenotypes.

The use of meta-analysis risk estimates for candidate genes in combination to predict coronary heart disease risk.

Abstract: Although the risk for coronary heart disease (CHD) associated with single SNPs is modest it has been suggested that, in combination, several common risk-associated alleles could lead to a substantially better heart disease risk prediction. We have modelled this using 10 SNPs in ten candidate genes (APOB, NOS3, APOE, ACE, SERPINE1, MTHFR, ITGA2B, PON 1, LPL, and CETP) and their predicted summary risk estimates from meta-analysis. Based on published allele frequencies, approximately 29% of the general population would be expected to carry less than three risk alleles, approximately 55% would carry 3 or 4 risk alleles, 4% would have 6 and 1% 7 or more risk alleles. Compared to the mean of those with 3 or 4 risk associated genotypes, those with 6 and 7-or-more alleles have a significantly higher risk odds ratio (OR) of CHD (mean OR (95% Confidence Intervals), 1.70 (1.14 to 2.55); and 4.51 (2.89 to 7.04) respectively), while compared to those in the lowest decile of risk, those in the highest decile have a CHD odds ratio in the range of 3.05 (2.24 to 4.14). Taking into account age and the risk alleles carried, the mean 10 year probability for developing CHD for a 55 year old man was calculated to be 15% (8.6% to 24.8%), with nearly 1 in 5 having more than 20% risk. Whether this particular group of 10 SNPs will improve the accuracy of CHD predictions over the combination of classical risk factors in clinical use requires further experimental evidence.

Carrier frequency of a nonsense mutation in the adenosine deaminase (ADA) gene implies a high incidence of ADA-deficient severe combined immunodeficiency (SCID) in Somalia and a single, common haplotype indicates common ancestry.

Abstract: Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that causes immunodeficiency, varying from severe combined immunodeficiency (SCID) in the majority of cases to a less severe form in a small minority of patients. Five patients of Somali origin from four unrelated families, with severe ADA-SCID, were registered in the Greater London area. Patients and their parents were investigated for the nonsense mutation Q3X (ADA c7C>T), two missense mutations K80R (ADA c239A>G) and R142Q (ADA c425G>A), and a TAAA repeat located at the 3' end of an Alu element (AluVpA) positioned 1.1 kb upstream of the ADA transcription start site. All patients were homozygous for the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7. Among 207 Somali immigrants to Denmark, the frequency of ADA c7C>T and the maximum likelihood estimate of the frequency of the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7 were both 0.012 (carrier frequency 2.4%). Based on the analysis of AluVpA alleles, the ADA c7C/T mutation was estimated to be approximately 7,100 years old. Approximately 1 out of 5 - 10000 Somali children will be born with ADA deficiency due to an ADA c7C/T mutation, although within certain clans the frequency may be significantly higher. ADA-SCID may be a frequent immunodeficiency disorder in Somalia, but will be underdiagnosed due to the prevailing socioeconomic and nutritional deprivation.

Y-chromosomal binary haplogroups in the Japanese population and their relationship to 16 Y-STR polymorphisms.

Abstract: We investigated Y chromosomal binary and STR polymorphisms in 263 unrelated male individuals from the Japanese population and further examined the relationships between the two separate types of data. Using 47 biallelic markers we distinguished 20 haplogroups, four of which (D2b1/-022457, O3/-002611*, O3/-LINE1 del, and O3/-021354*) were newly defined in this study. Most haplogroups in the Japanese population are found in one of the three major clades, C, D, or O. Among these, two major lineages, D2b and O2b, account for 66% of Japanese Y chromosomes. Haplotype diversity of binary markers was calculated at 86.3%. The addition of 16 Y-STR markers increased the number of haplotypes to 225, yielding a haplotype diversity of 99.40%. A comparison of binary haplogroups and Y-STR type revealed a close association between certain binary haplogroups and Y-STR allelic or conformational differences, such as those at the DXYS156Y, DYS390m, DYS392, DYS437, DYS438 and DYS388 loci. Based on our data on the relationships between binary and STR polymorphisms, we estimated the binary haplogroups of individuals from STR haplotypes and frequencies of binary haplogroups in other Japanese, Korean and Taiwanese Han populations. The present data will enable researchers to connect data from binary haplogrouping in anthropological studies and Y-STR typing in forensic studies in East Asian populations, especially those in and around Japan.

On the Usage of HWE for Identifying Genotyping Errors

Abstract: A recent publication by Zou & Donner (2006) discussed the merits of testing Hardy-Weinberg Equilibrium (HWE) in the setting of unmatched case-control association studies. Specifically, the authors highlighted that testing for HWE should not be used as a criterion for identifying single nucleotide polymorphisms (SNPs) with genotyping errors. The authors went on to discuss the potential problems associated with a two-stage analysis procedure, which incorporates checks for adherence to HWE prior to performing the association analyses.

Haplotype structure of FSHB, the beta-subunit gene for fertility-associated follicle-stimulating hormone: possible influence of balancing selection.

Abstract: Follicle-stimulating hormone (FSH) is essential for human reproduction. The unique functions of this hormone are provided by the FSH receptor-binding beta-subunit encoded by the FSHB gene. Resequencing and genotyping of FSHB in three European, two Asian and one African population, as well as in the great apes (chimpanzee, gorilla, orangutan), revealed low diversity and significant excess of polymorphisms with intermediate frequency alleles. Statistical tests for FSHB showed deviations from neutrality in all populations suggesting a possible effect of balancing selection. Two core haplotypes were identified (carried by 76-96.6% of each population's sample), the sequences of which are clearly separated from each other. As fertility most directly affects an organism's fitness, the carriers of these haplotypes have apparently had more success in human history to contribute to the next generation. There is a preliminary observation suggesting that the second most frequent FSHB haplotype may be associated with rapid conception success in females. Interestingly, the same haplotype is related to an ancestral FSHB variant shared with the ancestor of the great apes. The determination of the functional consequence of the two core FSHB variants may have implications for understanding and regulating human fertility, as well as in assisting infertility treatments.

Interrelationship and familiality of dyslexia related quantitative measures.

Abstract: Dyslexia is a complex gene-environment disorder with poorly understood etiology that affects about 5% of school-age children. Dyslexia occurs in all languages and is associated with a high level of social and psychological morbidity for the individual and their family; approximately 40-50% have persistent disability into adulthood. The core symptoms are word reading and spelling deficits, but several other cognitive components influence the core phenotype. A broad spectrum of dyslexia related phenotypes, including phonological decoding, phoneme awareness, orthographic processing, short-term memory, rapid naming and basic mathematical abilities, were investigated in large sample of 287 German dyslexia families. We explored the interrelationship between the component phenotypes using correlation and principal component analyses (PCA). In addition, we estimated familiality for phenotypes as well as for the factors suggested by PCA. The correlation between the component phenotypes varied between -0.1 and 0.7. The PCA resulted in three factors: a general dyslexia factor, a speed of processing factor and a mathematical abilities factor. The familiality estimates of single components and factors ranged between 0.25 and 0.63. Instead of analyzing single dyslexia-related components, multivariate analyses including factor analytic approaches may help in the identification of susceptibility genes.

Evidence for association of polymorphisms in CYP2J2 and susceptibility to essential hypertension.

Abstract: Summary Objective Evidence from animal models and human studies suggests that CYP2J2 plays a mechanistic role in the development of hypertension. The present study aims to investigate the potential genetic contribution of the CYP2J2 gene to the etiology of essential hypertension (EH) and individual blood pressure. Methods We selected eight polymorphisms in/or around the CYP2J2 gene and performed a case-control association study involving 841 Han Chinese subjects, including 415 unrelated hypertensives and 426 age-, gender- and area-matched normotensives. Results Three functionally identified variants (CYP2J2 *2, *7 and CYP2J2 *8) and SNP rs11572182 represented rare polymorphisms in Han Chinese. However, the difference in rs1155002 genotype distribution between hypertensive and healthy subjects was close to significance (P = 0.06) in the whole sample. Interestingly, significant evidence for an association with rs1155002 was found in females when stratified by gender. In females, the TT homozygote of rs1155002 seems to be a risk factor for hypertension (p = 0.014). In addition, ANOVA analysis suggested TT carriers had significantly higher systolic blood pressure (p = 0.016). The genotype frequencies for rs10493270, rs1180273 and rs1324491 revealed no statistically significant differences. Likewise, four-marker haplotype frequencies showed no significant differences between cases and controls. Conclusion Our data provide strong evidence that the CYP2J2 gene is a susceptibility factor for essential hypertension, especially in females, and influences individual systolic blood pressure in the Chinese Han population.

The Effects of SNP Genotyping Errors on the Power of The Cochran‐Armitage Linear Trend Test for Case/Control Association Studies

Abstract: The questions addressed in this paper are: What single nucleotide polymorphism (SNP) genotyping errors are most costly, in terms of minimum sample size necessary (MSSN) to maintain constant asymptotic power and significance level, when performing case-control studies of genetic association applying the Cochran-Armitage trend test? And which trend test or chi2 test is more powerful under standard genetic models with genotyping errors? Our strategy is to expand the non-centrality parameter of the asymptotic distribution of the trend test to approximate the MSSN using a Taylor series linear in the genotyping error rates. We apply our strategy to example scenarios that assume recessive, dominant, additive, or over-dominant disease models. The most costly errors are recording the more common homozygote as the less common homozygote, and the more common homozygote as the heterozygote, with MSSN that become indefinitely large as the minor SNP allele frequency approaches zero. Misclassifying the heterozygote as the less common homozygote is costly when using the recessive trend test on data from a recessive model. The chi2 test has power close to, but less than, the optimal trend test and is never dominated over all genetic models studied by any specific trend test.

Migration rates and genetic structure of two Hungarian ethnic groups in Transylvania, Romania.

Abstract: Transylvania's ethnic mosaic is composed of Romanians, German Saxons and Hungarians. The ethnic groups of the Hungarian minority that settled in Romania show differences in dialects, customs and religious affiliations. In this study entire mtDNA control region sequences from 360 individuals of Hungarian ethnicity from two populations (the Csango and the Szekely), settled in the historical region of Transylvania in Romania, were generated and analyzed following high quality sequencing standards. Phylogenetic analyses were used for haplogroup determination, quasi-median network analyses were applied for the visualization of character conflicts, and median joining reconstructions were used for depicting haplotype structures. Affiliation of haplotypes to major west Eurasian haplogroups was confirmed using coding region SNPs. Gene flow between the two populations was low and biased towards a higher migration rate from the Csango to the Szekely than vice versa. Phylogeographic analyses revealed effects of genetic isolation within the Csango population, which is, in its genetic structure, clearly different from the Szekely population. The pronounced genetic divergence between the two populations is in sharp contrast to the expectation of high genetic similarity due to the close geographic proximity of their native homelands. The population data will be incorporated in the EMPOP database (http://www.empop.org).

Mitochondrial and Y Chromosome Diversity in the English‐Speaking Caribbean

Abstract: Summary The transatlantic slave trade lasted over three centuries and represents one of the largest forced migrations in human history. The biological repercussions are not well understood especially in African-Caribbean populations. This paper explores the effects of the forced migration, isolation, and admixture on genetic diversity using mitochondrial and Y chromosome markers for 501 individuals from Dominica, Grenada, Jamaica, St. Kitts, St. Lucia, St. Thomas, St. Vincent, and Trinidad. Genetic diversity and population genetic structure analyses of mitochondrial data and Y chromosome data indicate that there was no post-migration loss in genetic diversity in the African derived lineages. Genetic structure was observed between the islands for both genetic systems. This may be due to isolation, differences in the number and source of Africans imported, depopulation of indigenous populations, and/or differences in colonization history. Nearly 10% of the individuals belonged to a non-African mitochondrial haplogroup. In contrast, Y chromosome admixture estimates showed that there was nearly 30% European contribution to these Caribbean populations. This study sheds light on the history of Africans in the Americas as well as contributing to our understanding of the nature and extent of diversity within the African Diaspora.

Common polymorphisms in the CACNA1H gene associated with childhood absence epilepsy in Chinese Han population.

Abstract: Variants with a relatively high frequency in the CACNA1H gene have previously been identified in cases of childhood absence epilepsy (CAE) in the Chinese Han population most of which are located in exons 6 to 12. In present study we attempted to further investigate whether the CACNA1H gene is associated with CAE. Exons 6 to 12 of CACNA1H gene were sequenced in samples of 100 CAE trios recruited consecutively, and 191 normal human controls. Single nucleotide polymorphisms (SNPs) were studied in both single locus and haplotype analyses in 218 CAE trios, of which 118 trios were selected from our previous research. Case-control comparisons and the transmission disequilibrium test (TDT) both supported a coding SNP (cSNP) rs9934839 (R603R) in exon 9 as being close related to CAE. The carriers of the G allele of rs9934839 had a 3-fold higher risk of CAE than non-carriers. Moreover, another cSNP rs8044363 was predicted to be connected directly with CAE in a Bayesian network. In addition, two haplotypes consisting of five cSNPs in the region of CACNA1H were statistically associated with CAE. Our research provides new evidence to further support the hypothesis that CACNA1H may be an important susceptibility gene for CAE in the Chinese Han population.

The missing ApoE allele.

Abstract: The human apoE gene (APOE, GenBank accession AF261279) shows a common polymorphism, with the three epsilon2, epsilon3 and epsilon4 alleles resulting from the haplotypes of two C-->T SNPs. However, whereas the three common T-T, T-C and C-C haplotypes corresponding to the epsilon2, epsilon3 and epsilon4 alleles are well known, the last C-T haplotype (GenBank accession AY077451), encoding a fourth apoE allele, has rarely been reported. We detected this fourth allele in a Caucasian patient with motor neuron disease (MND). According to the literature we refer to this allele as epsilon3r. Although several explanations may be proposed for its formation, the existence of this fourth allele is consistent with the evolutionary hypothesis generally accepted for the apoE alleles. The rarity and physiological role of epsilon3r remains to be explained, and requires further investigation.

The fate of 12 recessive mutations in a single village.

Abstract: Summary In a Muslim Arab village, relatively isolated because of the preference of consanguineous marriages, we studied the fate of 12 mutations in 5 different genes. The study was based on carriers detected among relatives of affected patients and of carriers discovered in a random sample of 424 adults. Most of the mutations have been introduced by a carrier(s) originating from another village, but a few have been de novo events. Mutations that are very frequent in the entire village were introduced soon after the foundation of the village. Examples of such mutations are [GBJ2, 35Gdel] and [MEFV, M680I], with a carrier frequency of 7.8% and 6.2%, respectively. Many of the other mutations that are rare were introduced recently into the village and are frequent only among the descendants of the first couple carrying the mutation. For instance all the carriers of [ARSA, Q190H], responsible for metachromatic leukodystrophy, were found among the 218 descendants of a couple who were living in the village 4 generations ago. Since the village is typical for the region this study allows for some general conclusions to be drawn. In a population with a high degree of inbreeding the diagnosis of a single family with a patient(s) affected with a recessive disorder points to a recent event, while the finding of a rare disease in several families from an inbred population points to an older mutation. Mutations are often “exported” from one population to another by marriage. In the new inbred population this novel mutation will either be lost or will become frequent as the result of a founder effect. These observations are important for genetic counselling in the case of a recent mutation, since only the descendants of the founder couple are at risk, while in the case of older mutations the risk may be for the entire village. In the case of those frequent ancient mutations, the risk for a relative of an affected individual will be similar whether he marries a close relative or any random individual in the village.

Molecular Epidemiology of Phenylalanine Hydroxylase Deficiency in Southern Italy: a 96% Detection Rate with Ten Novel Mutations

Abstract: Hyperphenylalaninemia (HPA) comprises a group of autosomal recessive disorders mainly caused by phenylalanine hydroxylase (PAH) gene mutations. We investigated PAH mutations in 126 HPA patients from Southern Italy who were identified in a neonatal screening program. The promoter, coding and exon-flanking intronic sequences of the PAH gene were amplified and sequenced. Mutations were identified in 240/249 alleles (detection rate: 96.4%). We found 60 gene variants; the most frequent were p.R261Q (15.7% of alleles), p.A403V (11.6% of alleles) and c.1066-11G > A (8.8% of alleles). The remaining mutations were rare, and ten are novel. This mutation epidemiology differs from that reported for Northern Italy and other European countries. We also identified several discordant genotype/phenotype correlations. About two-thirds of all mild phenylketonuria patients showed at least one tetrahydrobiopterin (BH4)-responsive mutation, and are thus candidates for a customized therapeutic approach.

Genetic analysis of FAM46A in Spanish families with autosomal recessive retinitis pigmentosa: characterisation of novel VNTRs.

Abstract: Retinitis pigmentosa (RP) is a group of retinal dystrophies characterised primarily by rod photoreceptor cell degeneration. Exhibiting great clinical and genetic heterogeneity, RP be inherited as an autosomal dominant (ad) and recessive (ar), X-linked (xl) and digenic disorder. RP25, a locus for arRP, was mapped to chromosome 6p12.1-q14.1 where several retinal dystrophy loci are located. A gene expressed in the retina, FAM46A, mapped within the RP25 locus, and computational data revealed its involvement in retinal signalling pathways. Therefore, we chose to perform molecular evaluation of this gene as a good candidate in arRP families linked to the RP25 interval. A comprehensive bioinformatic and retinal tissue expression characterisation of FAM46A was performed, together with mutation screening of seven RP25 families.Herein we present 4 novel sequence variants, of which one is a novel deletion within a low complexity region close to the initiation codon of FAM46A. Furthermore, we have characterised for the first time a coding tandem variation in the Caucasian population.This study reports on bioinformatic and moleculardata for the FAM46A gene that may give a wider insight into the putative function of this gene and its pathologic relevance to RP25 and other retinal diseases mapping within the 6q chromosomal interval.