Differentiation of Caucasians and Chinese at Bone Mass Candidate Genes: Implication for Ethnic Difference of Bone Mass

Bone mineral density (BMD) is an important risk factor for osteoporosis and has strong genetic determination. While average BMD differs among major ethnic groups, several important candidate genes have been shown to underlie BMD variation within populations of the same ethnicity. To investigate whether important candidate genes may contribute to ethnic differences in BMD, we studied the degree of genetic differentiation among several important candidate genes between two major ethnic groups: Caucasians and Chinese. The genetic variability of these two populations (1131 randomly selected individuals) was studied at six restriction sites exhibiting polymorphisms of five important candidate genes for BMD: the BsaHI polymorphism of the calcium‐sensing receptor (CASR) gene, the SacI polymorphism of the α₂HS‐glycoprotein (AHSG) gene, the PvuII and XbaI polymorphisms of the estrogen receptor α (ESR1) gene, the ApaI polymorphism of the vitamin D receptor (VDR) gene, and the BstBI polymorphism of the parathyroid hormone (PTH) gene. The two ethnic groups showed significant allelic and genotypic differentiation of all the polymorphisms studied. The mean F_ST was 0.103, which significantly differed from zero (P < 0.01) . The Chinese population had lower mean heterozygosity (0.331) than the Caucasian one (0.444); the CASR‐BsaHI and PTH‐BstBI polymorphisms contributed most significantly to this difference. Analysis of the intra‐ and inter‐population variability suggests that various types of natural selection may affect the observed patterns of variation at some loci. If some of the candidate genes we studied indeed underlie variation in BMD, their population differentiation revealed here between ethnic groups may contribute to understanding ethnic difference in BMD.     

Identification of Quantitative Trait Loci and Candidate Genes Influencing Ethanol Sensitivity in Honey Bees

Invertebrate models have greatly furthered our understanding of ethanol sensitivity and alcohol addiction. The honey bee (Apis mellifera), a widely used behavioral model, is valuable for comparative studies. A quantitative trait locus (QTL) mapping experiment was designed to identify QTL and genes influencing ethanol vapor sensitivity. A backcross mating between ethanol-sensitive and resistant lines resulted in worker offspring that were tested for sensitivity to the sedative effects of alcohol. A linkage map was constructed with over 500 amplified fragment length polymorphism (AFLP) and sequence-tagged site (STS) markers. Four QTL were identified from three linkage groups with log of odds ratio (LOD) scores of 2.28, 2.26, 2.23, and 2.02. DNA from markers within and near QTL were cloned and sequenced, and this data was utilized to integrate our map with the physical honey bee genome. Many candidate genes were identified that influence synaptic transmission, neuronal growth, and detoxification. Others affect lipid synthesis, apoptosis, alcohol metabolism, cAMP signaling, and electron transport. These results are relevant because they present the first search for QTL that affect resistance to acute ethanol exposure in an invertebrate, could be useful for comparative genomic purposes, and lend credence to the use of honey bees as biomedical models of alcohol metabolism and sensitivity. Edited by Yong-Kyu Kim.     

Expanding the spectrum of Grik2 mutations: intellectual disability,behavioural disorder,epilepsy and dystonia

Isolated congenital anosmia (ICA) is a rare disorder, where otherwise healthy individuals present with an inability to smell since birth. A list of studies have described the genes involved in syndromic anosmia; however, the genetics of ICA is still in its infancy. Studies in mice show that the cyclic nucleotide‐gated channel subunit CNGA2, expressed in the olfactory epithelium has a crucial role in olfactory signal transduction. We have identified a novel X‐linked stop mutation in CNGA2 (c.634C>T, p.R212*) in two brothers with ICA using exome sequencing. No additional mutations in CNGA2 were identified in a cohort of 31 non‐related ICA individuals. Magnetic resonance brain imaging revealed diminished olfactory bulbs and flattened olfactory sulci. This is the first report of a mutation in the cyclic nucleotide‐gated gene CNGA2 and supports the critical role of this gene in human olfaction.     

Olfactory ensheathing cells (OECs) and the treatment of CNS injury: advantages and possible caveats

One of the main research strategies to improve treatment for spinal cord injury involves the use of cell transplantation. This review looks at the advantages and possible caveats of using glial cells from the olfactory system in transplant-mediated repair. These glial cells, termed olfactory ensheathing cells (OECs), ensheath the axons of the olfactory receptor neurons. The primary olfactory system is an unusual tissue in that it can support neurogenesis throughout life. In addition, newly generated olfactory receptor neurons are able to grow into the CNS environment of the olfactory bulb tissue and reform synapses. It is thought that this unique regenerative property depends in part on the presence of OECs. OECs share some of the properties of both astrocytes and Schwann cells but appear to have advantages over these and other glial cells for CNS repair. In particular, OECs are less likely to induce hypertrophy of CNS astrocytes. As well as remyelinating demyelinated axons, OEC grafts appear to promote the restoration of functions lost following a spinal cord lesion. However, much of the evidence for this is based on behavioural tests, and the mechanisms that underlie their potential benefits in transplant-mediated repair remain to be clarified.     

Olfactory epithelium and ontogeny of the nasal chambers in the bowhead whale (Balaena mysticetus)

In a species of baleen whale, we identify olfactory epithelium that suggests a functional sense of smell and document the ontogeny of the surrounding olfactory anatomy. Whales must surface to breathe, thereby providing an opportunity to detect airborne odorants. Although many toothed whales (odontocetes) lack olfactory anatomy, baleen whales (mysticetes) have retained theirs. Here, we investigate fetal and postnatal specimens of bowhead whales (Balaena mysticetus). Computed tomography (CT) reveals the presence of nasal passages and nasal chambers with simple ethmoturbinates through ontogeny. Additionally, we describe the dorsal nasal meatuses and olfactory bulb chambers. The cribriform plate has foramina that communicate with the nasal chambers. We show this anatomy within the context of the whole prenatal and postnatal skull. We document the tunnel for the ethmoidal nerve (ethmoid foramen) and the rostrolateral recess of the nasal chamber, which appears postnatally. Bilateral symmetry was apparent in the postnatal nasal chambers. No such symmetry was found prenatally, possibly due to tissue deformation. No nasal air sacs were found in fetal development. Olfactory epithelium, identified histologically, covers at least part of the ethmoturbinates. We identify olfactory epithelium using six explicit criteria of mammalian olfactory epithelium. Immunohistochemistry revealed the presence of olfactory marker protein (OMP), which is only found in mature olfactory sensory neurons. Although it seems that these neurons are scarce in bowhead whales compared to typical terrestrial mammals, our results suggest that bowhead whales have a functional sense of smell, which they may use to find prey.     

Immunohistochemical and Histochemical Characteristics of the Olfactory System of the Guppy,Poecilia reticulata (Teleostei,Poecilidae)

Olfaction in fish has been studied using preferentially macrosmatic species as models. In the present research, the labelling patterns of different neuronal markers and lectins were analyzed in the olfactory neurons and in their bulbar axonal endings in the guppy Poecilia reticulata, belonging to the group of microsmatic fish. We observed that calretinin immunostaining was confined to a population of olfactory receptor cells localized in the upper layers of the sensory mucosa, probably microvillous neurons innervating the lateral glomerular layer. Immunoreactivity for S100 proteins was mainly evident in crypt cells, but also in other olfactory cells belonging to subtypes projecting in distinct regions of the bulbs. Protein gene product 9.5 (PGP 9.5) was not detected in the olfactory system of the guppy. Lectin binding revealed the presence of N‐acetylglucosamine and α‐N‐acetylgalactosamine residues in the glycoconjugates of numerous olfactory neurons ubiquitously distributed in the mucosa. The low number of sugar types detected suggested a reduced glycosidic variability that could be an index of restricted odorant discrimination, in concordance with guppy visual‐based behaviors. Finally, we counted few crypt cells which were immunoreactive for S100 and calretinin. Crypt cells were more abundant in guppy females. This difference is in accordance with guppy gender‐specific responses to pheromones. Cells immunoreactive to calretinin showed no evidence of ventral projections in the bulbs. We assumed the hypothesis that their odorant sensitivity is not strictly limited to pheromones or sexual signals in general. Anat Rec, 2009. © 2009 Wiley‐Liss, Inc.     

A multi‐centre study of candidate genes for wheeze and allergy: the International Study of Asthma and Allergies in Childhood Phase 2

Background Common polymorphisms have been identified in genes suspected to play a role in asthma. We investigated their associations with wheeze and allergy in a case–control sample from Phase 2 of the International Study of Asthma and Allergies in Childhood. Methods We compared 1105 wheezing and 3137 non‐wheezing children aged 8–12 years from 17 study centres in 13 countries. Genotyping of 55 candidate single nucleotide polymorphisms (SNPs) in 14 genes was performed using the Sequenom System. Logistic regression models were fitted separately for each centre and each SNP. A combined per allele odds ratio and measures of heterogeneity between centres were derived by random effects meta‐analysis. Results Significant associations with wheeze in the past year were detected in only four genes (IL4R, TLR4, MS4A2, TLR9, P<0.05), with per allele odds ratios generally <1.3. Variants in IL4R and TLR4 were also related to allergen‐specific IgE, while polymorphisms in FCER1B (MS4A2) and TLR9 were not. There were also highly significant associations (P<0.001) between SPINK5 variants and visible eczema (but not IgE levels) and between IL13 variants and total IgE. Heterogeneity of effects across centres was rare, despite differences in allele frequencies. Conclusions Despite the biological plausibility of IgE‐related mechanisms in asthma, very few of the tested candidates showed evidence of association with both wheeze and increased IgE levels. We were unable to confirm associations of the positional candidates DPP10 and PHF11 with wheeze, although our study had ample power to detect the expected associations of IL13 variants with IgE and SPINK5 variants with eczema.     

On the Olfactory Anatomy in an Archaic Whale (Protocetidae,Cetacea) and the Minke Whale Balaenoptera acutorostrata (Balaenopteridae,Cetacea)

The structure of the olfactory apparatus is not well known in both archaic and extant whales; the result of poor preservation in most fossils and locational isolation deep within the skulls in both fossil and Recent taxa. Several specimens now shed additional light on the subject. A partial skull of an archaic cetacean is reported from the Pamunkey River, Virginia, USA. The specimen probably derives from the upper middle Eocene (Piney Point Formation) and is tentatively assigned to the Protocetidae. Uncrushed cranial cavities associated with the olfactory apparatus were devoid of sediment. CT scans clearly reveal the dorsal nasal meatus, ethmoturbinates within the olfactory recess, the cribriform plate, the area occupied by the olfactory bulbs, and the olfactory nerve tract. Several sectioned skulls of the minke whale (Balaenoptera acutorostrata) were also examined, and olfactory structures are remarkably similar to those observed in the fossil skull from the Pamunkey River. One important difference between the two is that the fossil specimen has an elongate olfactory nerve tract. The more forward position of the external nares in extant balaenopterids when compared with those of extant odontocetes is interpreted to be the result of the need to retain a functional olfactory apparatus and the forward position of the supraoccipital/cranial vertex. An increase in the distance between the occipital condyles and the vertex in balaenopterids enhances the mechanical advantage of the epaxial musculature that inserts on the occiput, a specialization that likely stabilizes the head of these enormous mammals during lunge feeding. Anat Rec, 2013. © 2012 Wiley Periodicals, Inc.     

Candidate Genes and Single Nucleotide Polymorphisms (SNPs) in the Study of Human Disease

The genomic revolution has generated an extraordinary resource, the catalog of variation within the human genome, for investigating biological, evolutionary and medical questions. Together with new, more efficient platforms for high-throughput genotyping, it is possible to begin to dissect genetic contributions to complex trait diseases, specifically examining common variants, such as the single nucleotide polymorphism (SNP). At the same time, these tools will make it possible to identify determinants of disease with the expectation of eventually, tailoring therapies based upon specific profiles. However, a number of methodological, practical and ethical issues must be addressed before the analysis of genetic variation becomes a standard of clinical medicine. The currents of variation in human biology are reviewed here, with a specific emphasis on future challenges and directions.     

APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intima-media thickness in healthy men (the Stanislas cohort)

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) inter-individual variability and 16 polymorphisms of 11 genes associated with cardiovascular risk factors (genes among lipid and homocysteine metabolisms, blood viscosity, platelet aggregation, leukocyte adhesion and renin-angiotensin system). CIMT was measured by high resolution B-mode ultrasonography in an healthy population of 77 men and 84 women, aged 35-54 years and selected from a French Cohort: the Stanislas Cohort. The polymorphisms studied were genotyped by a multilocus approach. Statistical analyses were carried out by ANOVA, after adjustment of CIMT for age, body mass index, and smoking, and by multiple regression analyses. No association was found with APOB Thr71Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T, and SELE Ser128Arg, polymorphisms neither in men nor in women. Although, in women we did not find any association for APOC3 3206T/G, 3175C/G, 1100C/T, CETP Ile405Val, MTHFR 677C/T and fibrinogen -455G/A polymorphisms; in men these polymorphisms were associated with CIMT variability (p< or =0.01; p< or =0.05). The most interesting finding was that altogether these genes in men were able to explain a considerable part, 20.6%, of CIMT variability. Therefore, our study gives a new opportunity to understand CIMT variability.     

Common subtypes of idiopathic generalized epilepsies: Lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). A trait locus (EBN1) for a rare subtype of IGEs, the benign neonatal familial convulsions, and a susceptibility gene (EEGV1) for the common human low-voltage electroencephalogram have been mapped close together with D20S19 to the chromosomal region 20q13.2. Both loci are potential candidates for the susceptibility to IGE spectra with age-related onset beyond the neonatal period. The present study tested the hypothesis that a putative susceptibility locus linked to D20S19 predisposes to spectra of IGEs with age-related onset from childhood to adolescence. Linkage analyses were conducted in 60 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy. Our results provide evidence against linkage of a putative susceptibility gene for four hierarchically broadened IGE spectra with D20S19 assuming tentative single-locus genetic models. The extent of an “exclusion region” (lod scores below − 2) varied from 0.5 cM up to 22 cM on either side of D20S19 depending on the trait assumed. These results are contrary to the expectation that a susceptibility gene in vicinity to D20S19 confers a common major gene effect to the expression of IGE spectra with age-related onset from childhood to adolescence. © 1996 Wiley-Liss, Inc.     

Human Leukocyte Antigens (HLA) Class I and Class II on Sperm Cells Studied at the Serological,Cellular, and Genomic Levels

ABSTRACT: The expression of human leukocyte antigens (HLA) on highly purified human ejaculated sperm cells was studied using the sensitive enzyme-linked immunosorbent assay (ELISA) technique and a wide panel of monoclonal antibodies to class I and class II HLA. In addition, the stimulatory capacity of these cells was tested in mixed cultures of lymphocytes and spermatozoa, and the levels of RNA homologous to the HLA class I and class II genes were determined. The results obtained using the ELISA indicate that the class I and class II HLA serologically defined antigens are weakly expressed on the cell surface of the mature spermatozoa. Highly purified sperm cells consistently stimulated heterologous lymphocytes but not when HLA-DR compatibility was observed between stimulator and responder. The proliferative response of lymphocytes induced by sperm cells was lower than the response obtained in a lymphocyte-lymphocyte combination, though the kinetics of the response were similar in both cases. In addition, it was found that spermatozoa contained RNA species homologous to HLA class II DRβ and DQβ genes sequences but not to HLA class I sequences. The levels of these RNA species were significantly reduced after interferon stimulation. Lymphocytes that served as positive control were found to contain RNA complementary to both HLA class I and class II genes.     

Candidate human papillomavirus (HPV) type 27b: nucleotide sequence and heterogeneity with HPV 27

More than 100 human papillomavirus (HPV) types have been reported as tumorigenic agents. HPV types 2 and 27 were identified in benign tumors and classified closely according to the sequence homology. An HPV type 2 related sequence was identified previously in an oral papilloma. However, the correct typing and sequencing was impossible at that time. A candidate HPV was cloned by the long-PCR technique from an oral papilloma and characterized by nucleotide sequence. This virus was basically HPV type 27, but there was some heterogeneity in comparison with the prototype. Most differences were nucleotide-sequence variations. Two of four-nucleotide insertions were frame shift, resulting in longer L1 protein than that of HPV 27.     

The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations

Congenital contractural arachnodactyly (CCA) is an extremely rare disease, due to mutations in the FBN2 gene encoding fibrillin-2. Another member of the fibrillin family, the FBN1 gene, is involved in a broad phenotypic continuum of connective-tissue disorders including Marfan syndrome. Identifying not only what is in common but also what differentiates these two proteins should enable us to better comprehend their respective functions and better understand the multitude of diseases in which these two genes are involved. In 1995 we created a locus-specific database (LSDB) for FBN1 mutations with the Universal Mutation Database (UMD) tool. To facilitate comparison of identified mutations in these two genes and search for specific functional areas, we created an LSDB for the FBN2 gene: the UMD-FBN2 database. This database lists 26 published and six newly identified mutations that mainly comprise missense and splice-site mutations. Although the number of described FBN2 mutations was low, the frequency of joint dislocation was significantly higher with missense mutations when compared to splice site mutations.     

Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2)

Kallmann syndrome (KAL) combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is due to Gonadotropin Releasing Hormone (GnRH) deficiency and anosmia is related to hypoplasia of the olfactory bulbs. Occasional symptoms include renal agenesis, bimanual synkinesia, cleft lip palate, dental agenesis. KAL is genetically heterogeneous and two genes have so far been identified, namely KAL1 (Xp22.3) and FGFR1/KAL2 (8p12), which underlie the X chromosome‐linked form and an autosomal dominant form of the disease, respectively. We studied a cohort of 98 unrelated Caucasian KAL patients. We identified KAL1 mutations in 14 patients, of which 7 (c.3G>A (p.M1?), g.IVS1+1G>T, c.570_571insA (p.R191fsX14), c.784G>C (p.R262P), c.958G>T (p.E320X), c.1651_1654delinsAGCT (p.P551_E552delinsSX), c.1711T>A (p.W571R)) have not been previously reported. In addition, we found FGFR1 mutations in 7 patients, namely c.303G>A (p.V102I), C.385A>C (p.D129A), c.810G>A (p.V273M), c.1093_1094delAG (p.R365fsX41), c.1561G>A (p.A520T), c.1836_1837insT (p.Y613fsX42), c.2190C>G (p.Y730X), all of which were novel mutations. In this study, unilateral renal agenesis and bimanual synkinesia were exclusively found associated with KAL1mutations, cleft palate and dental agenesia with FGFR1mutations. © 2004 Wiley‐Liss, Inc.     

Origin and spread of a common deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity

Mucolipidosis II (ML II alpha/beta), or I-cell disease, is a rare genetic disease in which activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent. GlcNAc-phosphotransferase is a multimeric enzyme encoded by two genes, GNPTAB and GNPTG. A spectrum of mutations in GNPTAB has been recently reported to cause ML II alpha/beta. Most of these mutations were found to be private or rare. However, the mutation c.3503_3504delTC has been detected among Israeli and Palestinian Arab-Muslim, Turkish, Canadian, Italian, Portuguese, Irish traveller and US patients. We analysed 44 patients who were either homozygous or compound heterozygous for this deletion (22 Italians, 8 Arab-Muslims, 1 Turk, 3 Argentineans, 3 Brazilians, 2 Irish travellers and 5 Portuguese) and 16 carriers (15 Canadians and 1 Italian) for three intragenic polymorphisms: c.-41_-39delGGC, c.18G>A and c.1932A>G as well as two microsatellite markers flanking the GNPTAB gene (D12S1607 and D12S1727). We identified a common haplotype in all chromosomes bearing the c.3503_3504delTC mutation. In summary, we showed that patients carrying the c.3503_3504delTC deletion presented with a common haplotype, which implies a common origin of this mutation. Additionally, the level of diversity observed at the most distant locus indicates that the mutation is relatively ancient (around 2063 years old), and the geographical distribution further suggests that it probably arose in a peri-Mediterranean region.     

Extraintestinal Salmonellosis in a General Hospital (1991 to 1996): Relationships between Salmonella Genomic Groups and Clinical Presentations

Episodes of extraintestinal salmonellosis treated at a general hospital (1,522 beds) over a 6-year period (1991 to 1996) were characterized by the analysis of phenotypic and genotypic traits of Salmonella organisms and clinical data from medical reports. Extraintestinal salmonellosis accounted for 8% of all salmonellosis episodes. Fifty-two medical reports, dealing with 6 cases of typhoid fever, 32 cases of bacteremia, and 14 focal infections, were reviewed. All cases of typhoid fever except 1, 7 cases of bacteremia, and 5 focal infections were not related to any underlying disease or predisposing factors, while 25 cases of bacteremia and 9 focal infections were associated with some of these risk factors. All typhoid isolates and 65.4% of the nontyphoid isolates were susceptible to antimicrobials. Fifty-one nontyphoid strains were analyzed and assigned to 21 genomic groups, which were defined by serotype, combined ribotype, and combined randomly amplified polymorphic DNA type (each genomic group could include organisms differing in some phenotypic traits). The relationships between genomic groups and clinical presentations were traced. Organisms causing 22 episodes (17 episodes of bacteremia, 2 of pneumonia, 1 of peritonitis, 1 of pyelonephritis, and 1 of cystitis) belonged to a prevalent Salmonella enterica serotype Enteritidis genomic group, which included organisms assigned to four phage types, five biotypes, and four resistance patterns, causing infections in patients with and without risk factors. Seven other genomic groups, 4 Enteritidis groups (associated with both bacteremia and focal infections), 2 Typhimurium groups (one associated with bacteremia and the other with focal infections) and 1 Brandenburg group (associated with bacteremia) included two or more strains, and the remaining 13 genomic groups consisted of only one strain each.     

Mouse models of patent ductus arteriosus (PDA) and their relevance for human PDA

The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling pathways lead to constriction and permanent closure of the DA. The persistent patency of the DA (PDA) is a common disorder in preterm infants, yet the underlying causes of PDA are not fully defined. Although limits on the availability of human DA tissues prevent comprehensive studies on the mechanisms of DA function, mouse models have been developed that reveal critical pathways in DA regulation. Over 20 different transgenic models of PDA in mice have been described, with implications for human DA biology. Similarly, we enumerate 224 human single-gene syndromes that are associated with PDA, including a small subset that consistently feature PDA as a prominent phenotype. Comparison and functional analyses of these genes provide insight into DA development and identify key regulatory pathways that may serve as potential therapeutic targets for the management of PDA.     

TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data

TP53 gene mutations are one of the most frequent somatic events in cancer. The IARC TP53 Database ( http://p53.iarc.fr ) is a popular resource that compiles occurrence and phenotype data on TP53 germline and somatic variations linked to human cancer. The deluge of data coming from cancer genomic studies generates new data on TP53 variations and attracts a growing number of database users for the interpretation of TP53 variants. Here, we present the current contents and functionalities of the IARC TP53 Database and perform a systematic analysis of TP53 somatic mutation data extracted from this database and from genomic data repositories. This analysis showed that IARC has more TP53 somatic mutation data than genomic repositories (29,000 vs. 4,000). However, the more complete screening achieved by genomic studies highlighted some overlooked facts about TP53 mutations, such as the presence of a significant number of mutations occurring outside the DNA‐binding domain in specific cancer types. We also provide an update on TP53 inherited variants including the ones that should be considered as neutral frequent variations. We thus provide an update of current knowledge on TP53 variations in human cancer as well as inform users on the efficient use of the IARC TP53 Database.