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Differential shuffling of native genetic diversity across introduced regions in a brown alga: aquaculture vs. maritime traffic effects.

Worldwide marine invaders, such as the brown alga Undaria pinnatifida, offer challenging models for unraveling the apparent paradox of sustainable settlement of exotic species over a large spectrum of environments. Two intergenic noncoding mitochondrial loci were found to be highly informative at the within-species level. Twenty-five haplotypes were found over the whole dataset (333 base pairs, 524 individuals, and 24 populations). The native range showed striking population genetic structure stemming from low diversity within and high differentiation among populations, a pattern not observed in the introduced range of this seaweed. Contrary to classical expectations of founding effects associated with accidental introduction of exotic species, most of the introduced populations showed high genetic diversity. At the regional scale, genetic diversity and sequence divergence showed contrasting patterns in the two main areas of introduction (Europe and Australasia), suggesting different processes of introduction in the two regions. Gene genealogy analyses point to aquaculture as a major vector of introduction and spread in Europe but implicate maritime traffic in promoting recurrent migration events from the native range to Australasia. The multiplicity of processes and genetic signatures associated with the successful invasion confirms that multiple facets of global change, e.g., aquaculture practices, alteration of habitats, and increased traffic, act in synergy at the worldwide level, facilitating successful pandemic introductions.

Aquaculture↗

Analysis of the French National Registry of unrelated bone marrow donors, using surnames as a tool for improving geographical localisation of HLA haplotypes.

The first statistical analysis of the French National Registry of volunteer bone marrow donors estimated the probabilities of haplotype frequencies separately for each of the 20 administrative regions of France. Here we propose to use donors' surnames to increase the accuracy of location of the donor's geographical origin. This approach allows us to estimate haplotype frequencies for administrative entities (90 departments) smaller than regions and to correct for bias resulting from recent mobility. We analysed 30,777 donors typed for HLA-A,B and 17,745 donors typed for HLA-A,B,DR,DQ. By using the donors' surnames, we identified common and rare haplotypes (those found in only one department) and estimated the degree of HLA polymorphism at the department level. We also identified departments with a distinctive genetic structure (for example, Paris, Corsica, Pyrenees and Meurthe-et-Moselle). By providing a more accurate geographical distribution of HLA polymorphisms in France, this study will enable us to optimise policies for recruiting bone marrow donors and to improve the fit between the donor file and patients' needs.

Algorithms↗

Mitochondrial markers in the ant Leptothorax rugatulus reveal the population genetic consequences of female philopatry at different hierarchical levels.

Leptothorax rugatulus, an abundant North American ant, displays a conspicuous queen size polymorphism that is related to alternative reproductive tactics. Large queens participate mainly in mating flights and found new colonies independent of their mother colony. In contrast, small queens do not found new colonies independently, but seek readoption into their natal nest which results in multiple-queen colonies (polygyny). Populations differ strongly in the ratio of small to large queens, the prevalent reproductive tactic and colony social structure, according to ecological parameters such as nest site stability and population density. This study compares the genetic structure of two strongly differing populations within the same mountain range. Data from microsatellites and mitochondrial DNA give no evidence for alien reproductives in polygynous colonies. The incidence of alien workers in colonies (as determined by mitochondrial haplotype) was low and did not differ between monogynous and polygynous colonies. We found significant population viscosity (isolation-by-distance) at the mitochondrial level in only the predominantly polygynous population, which supports the theoretical prediction that female philopatry leads to mtDNA-specific population structure. Nuclear and mitochondrial genetic diversity was similar in both populations. The genetic differentiation between the two investigated populations was moderate at the mitochondrial level, but not significantly different from zero when measured with microsatellites, which corroborates limited dispersal of females (but not males) at a larger scale.

Animals↗

mtDNA variation in the Chibcha Amerindian Huetar from Costa Rica.

The genetic variation in a Chibcha-speaking Amerindian tribe from lower Central America, the Huetar, was analyzed using nucleotide sequences of the hypervariable segments of the mitochondrial DNA (mtDNA) control region, the frequencies of 10 Amerindian-specific mtDNA haplotypes, and the regional distribution of private protein polymorphisms. The sequencing of 713 base pairs (bp) in the control regions of 27 individuals revealed 11 distinct lineages. These were defined by 24 variable sites and a 6-bp deletion between nucleotide pairs (np) 106 and 111. The 6-bp deletion is a new mtDNA marker that will be valuable for Amerindian taxonomic research. Control region sequences and mtDNA haplotype analyses reveal that Huetar mtDNAs are distributed in "Amerindian clusters" A, B, and D. A maximum-likelihood phylogenetic tree suggests a single origin for the 6-bp Huetar deletion in the sample. mtDNA haplotype analysis and the presence of previously characterized private protein variants (PEPA*F, TF*DCHI, and the absence of DI*A) show that the Huetar harbor polymorphisms of considerable antiquity, suggesting an early divergence from the regional founder gene pool for this population. The data also reflect a drastic constriction in population size, an evolutionary event with a proposed central effect on Huetar genetic structure.

Base Sequence↗

Population genetic structure and demographic history of the endemic Formosan lesser horseshoe bat (Rhinolophus monoceros).

Intraspecific phylogenies can provide useful insights into how populations have been shaped by historical and contemporary processes. Taiwan formed around 5 million years ago from tectonic uplift, and has been connected to mainland Asia several times since its emergence. A central mountain range runs north to south, bisecting the island, and potentially impedes gene flow along an east-west axis. The Formosan lesser horseshoe bat (Rhinolophus monoceros) is endemic to Taiwan, where it is found mainly at low altitude. To determine the population structure and the demographic and colonization history of this species, we examined variation in the mitochondrial DNA control region in 203 bats sampled at 26 sites. We found very high haplotype and nucleotide diversity, which decreased from the centre to the south and north. Population differentiation followed a pattern of isolation by distance, though most regional genetic variance was attributable to differences between the relatively isolated southern population and those from other regions. A haplotype network was consistent with these findings and also suggested a southward colonization, followed by subsequent secondary contact between the south and other regions. Mismatch distributions were used to infer a past population expansion predating the last glacial maximum, and a neighbour-joining tree showed that R. monoceros formed a monophyletic grouping with respect to its sister taxa. Taken together, our results suggest that this taxon arose from a single period of colonization, and that demographic growth followed in the late Pleistocene. Current genetic structure reflects limited gene flow, probably coupled with stepwise colonization in the past. We consider explanations for the persistence of the species through multiple glacial maxima.

Animals↗

Association between acute lymphoblastic leukemia and partial IgA deficiency in a young man--a family study.

We report on an unusual association between partial IgA deficiency and acute lymphoblastic leukemia in a young man. We also report results of the family study of immunoglobulin levels, sIgA B cells, in vitro IgA synthesis and molecular analysis of the structural C alpha genes. The IgA deficiency was present at diagnosis of leukemia prior to any therapy. The indirect arguments for a preexisting IgA deficiency are the absence of improvement of the IgA level during complete remission and especially the finding of a similar partial IgA deficiency in a sister who shared the same HLA haplotype, had a low percentage of sIgA B cells and decreased in vitro IgA production. The mother, who had a normal IgA serum level also had decreased in vitro IgA synthesis. No major structural C alpha gene defect was found. The relationship between acute lymphoblastic leukemia and IgA deficiency remains to be elucidated.

Adolescent↗

Association between chloroplast and mitochondrial lineages in oaks.

Patterns of chloroplast DNA (cpDNA) and mitochondrial DNA (mtDNA) variation were studied in 378 populations of oak trees sampled throughout the southern half of France. Six cpDNA haplotypes detected in a previous European survey and three new cpDNA haplotypes were found in this region. Two mitochondrial polymorphisms detected earlier by restriction analysis of PCR-amplified fragments alone, or in combination with single-strand conformation polymorphism (SSCP), were compared with the cpDNA data. Sequencing revealed the nature of the two mitochondrial mutations: a single-base substitution and a 4-bp inversion associated with a 22-bp hairpin secondary structure. The single-base substitution was then analyzed by allele-specific amplification. Results for the two cytoplasmic genomes were combined, which allowed the identification of 12 cpDNA-mtDNA haplotypes. The 4-bp mtDNA inversion has appeared independently in different cpDNA lineages. Given the peculiar nature of this mtDNA mutation, we suggest that intramolecular recombination leading to repeated inversions of the 4-bp sequence (rather than paternal leakage of one of the two genomes) is responsible for this pattern. Furthermore, the geographic locations of the unusual cpDNA-mtDNA associations (due to the inversion) usually do not match the zones of contact between divergent haplotypes. In addition, in southern France, the groupings of populations based on the mtDNA substitution were strictly congruent with those based on cpDNA. Because many populations that are polymorphic for both cpDNA and mtDNA have remained in contact since postglacial recolonization in this area without producing any new combination of cytoplasms involving the mitochondrial substitution, we conclude that paternal leakage is not a significant factor at this timescale. Such results confirm and expand our earlier conclusions based on controlled crosses.

Base Sequence↗

GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence.

Gamma-aminobutyric acid (GABA) A receptors are believed to mediate some of the physiological and behavioral actions of ethanol. Recent studies have suggested that genetic variants of the GABA-A receptor alpha2 subunit gene (GABRA2) are associated with alcohol dependence. The aim of this study is to confirm and extend the role of GABRA2 haplotypes in the liability to alcohol dependence. 291 (231 male) treatment-seeking alcohol-dependent individuals and 295 (153 male) control subjects were enrolled into the study. Characteristics of alcohol dependence were obtained using the SSAGA (semi-structured assessment of the genetics of alcoholism, German Version). Genotyping of 10 SNPs across the GABRA2 gene was performed following previous reports and using PCR. One genetic variant was detected to significantly differ between alcohol-dependent subjects and controls. Two common 8 SNP haplotypes and their complementary alleles were identified containing this SNP and were present in 89.9% of controls and 93.4% of the alcohol-dependent individuals. One of the haplotypes (T-C-A-C-A-T-T-C) was significantly associated with alcohol dependence and characteristics of alcohol withdrawal and severity of alcohol dependence (delirium tremens, withdrawal seizures). These findings support and extend the three previous studies implicating a GABA-A receptor subunit as contributing to the genetic risk for alcohol dependence. Possible implications of these findings are discussed.

Adult↗

Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure-function correlations of alphaIIbbeta3 integrin (ITGA2B, ITGB3).

The molecular basis of Glanzmann thrombasthenia (GT) was studied in 40 families from southern India. Of 23 identified mutations (13 in the alphaIIb (ITGA2B) gene and 10 in the beta3 (ITGB3) gene), 20 were novel and three were described previously. Three mutations in the beta3 gene-p.Leu143Trp (Leu117Trp), p.Tyr307Stop (Tyr281Stop), and p.Arg119Gln (Arg93Gln)-were detected in 12, three, and two families, respectively, with definite founder effects observed for the first two mutations. Alternative splicing was predicted in silico for the normal variant and a missense variant of the beta3 gene, and for 10/11 frameshift or nonsense mutations in alphaIIb or beta3. The prediction was confirmed experimentally for a c.2898_2902dupCCCCT mutation in exon 28 of the alphaIIb gene that induced exon skipping. Seven out of nine missense mutations substituted highly conserved amino acids buried in the proteins' cores, predicting structural abnormalities. Among these, a beta3 substitution, p.Cys39Gly (Cys13Gly) was found to cause intracellular degradation of the beta3 subunit, in contrast to previous findings that mutations at Cys435, the partner of Cys13 in a disulfide bond, cause constitutive activation of alphaIIbbeta3. The two patients with a beta3 Arg93Gln mutation had normal clot retraction, consistent with a recent finding that this substitution is associated with normal surface expression of alphaIIbbeta3. In conclusion, this study demonstrates that a variety of mutations account for GT in southern Indian patients, provides new insights into mRNA splicing, and highlights the role of specific amino acids in structure-function correlations of alphaIIbbeta3.

Alternative Splicing↗

RFLP analysis of mitochondrial DNA to evaluate genetic variation in striped red mullet (Mullus surmuletus L.) and red mullet (Mullus barbatus L.) populations.

The genetic differentiation of striped red mullet (Mullus surmuletus) and red mullet (Mullus barbatus) was investigated in 6 Mediterranean populations of each species by means of restriction fragment length polymorphism analysis of mitochondrial DNA. Three segments amplified by polymerase chain reaction (control region, COI, and 12S-16S ribosomal RNA) were digested with 20 restriction endonucleases, revealing 71 haplotypes for M. surmuletus and 30 for M. barbatus. For the two species nucleotide diversity was equally distributed within and among populations, leading to N(ST) values of 0.545 and 0.500 for M. surmuletus and M. barbatus, respectively. However, intrapopulation and interpopulation genetic structuring appeared to be much higher for M. surmuletus than for M. barbatus (1.88% vs. 0.46% of mean intrapopulation nucleotide diversity; 1.94% vs. 0.47% of mean interpopulation nucleotide diversity; 0.055% vs. 0.002% of net interpopulation divergence). Furthermore, 81.69% of the haplotypes observed for M. surmuletus were unique, whereas 70.29% of M. barbatus individuals were grouped in 3 common haplotypes. Given that fishing pressure and population sizes are similar for both species, this differentiation could be attributed to differences in biological parameters and life histories between the two species, coupled with oceanographic conditions prevailing in the studied area.

Journal Article↗

Homologous collagen-induced arthritis in rats and mice are associated with structurally different major histocompatibility complex DQ-like molecules.

Collagen-induced arthritis (CIA) in rats, induced with homologous type II collagen (CII), is a genetically more restricted disease and has better resemblance to rheumatoid arthritis by its chronic disease course, than CIA induced with heterologous CII. The DA strain is highly susceptible to CIA induced with homologous CII, while the Lewis strain is resistant. (DAxLew)F1 is susceptible and backcrossing to Lewis reveals a close, but not complete, association of both arthritis and CII responsiveness to the RT1a haplotype. Analyses of congenic strains on DA and Lewis backgrounds suggest that expression of a major histocompatibility complex class II Ba molecule, encoded from the RT1Ba locus, is associated with arthritis susceptibility and CII responsiveness. The second exons coding for the first domains of the alpha and beta chains of both the RT1a and RT1l haplotypes were sequenced and the deduced amino acid sequences compared with the corresponding molecule associated with susceptibility to CIA in the mouse (H-2 Aq). The sequences of the respective alleles revealed no obvious structural homology explaining the extensive similarities in the development of chronic autoimmune arthritis. Instead, this finding implies that different trimolecular constituents (i.e. class II, T cell receptor, and CII peptides) may yield an antigen presentation event that is able to trigger a similar autoaggressiveness in the two rodent species.

Amino Acid Sequence↗

Association between a variation in LRCH1 and knee osteoarthritis: a genome-wide single-nucleotide polymorphism association study using DNA pooling.

OBJECTIVE: To perform a large-scale association analysis of single-nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee. METHODS: We examined >25,000 SNPs located within approximately 14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case-control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression. RESULTS: The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as-yet-unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case-control groups. Additional subanalyses in case-control samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine-mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up-regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role. CONCLUSION: A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.

Aged↗

Phylogeography of the Northern short-tailed shrew, Blarina brevicauda (Insectivora: Soricidae): past fragmentation and postglacial recolonization.

Blarina brevicauda is distributed across the northeastern region of North America, in areas previously covered by Pleistocene glaciers. Previous molecular systematic study of the species in the genus Blarina suggested the presence of two distinct eastern and western phylogroups within B. brevicauda, in agreement with traditionally recognized semi-species. To expand the previous work, a collection of 76 individuals from 14 localities collected throughout the range of B. brevicauda was used to assess the mitochondrial (mt) cytochrome b genealogy for this species. Minimum evolution, maximum parsimony, analysis of molecular variance and nested clade analysis each supported the same conclusions of two well-differentiated and monophyletic east-west groups, separated by the Mississippi River. Denser sampling in areas immediately East of the Mississippi basin revealed further subdivision within the eastern phylogroup into an East-Central and an Appalachian clade. The western phylogroup differed from the eastern phylogroup by 2.5% mean absolute DNA sequence difference. About 65% of the genetic variance among samples was explained by the east-west subdivision alone. High haplotype diversities, low nucleotide diversities and unimodal mismatch distributions within subclades suggest recent expansion or diversification within each group. No phylogeographic structure was found within the western phylogroup, but genetic structure because of restricted gene flow and isolation by distance was inferred for the eastern group. The present distribution of B. brevicauda is best explained by past fragmentation and range expansion events during and following the Pleistocene glacial cycles.

Animals↗

Exclusive involvement of H-2Db or H-2Kd product in the interaction between T-killer lymphocytes and syngeneic H-2b or H-2d viral lymphomas.

It was demonstrated previously that the cytolysis of murine viral lymphoma cells by anti-murine sarcoma virus (MSV) syngeneic T-killer lymphocytes was restricted by some products of the H-2 complex. The respective role of the products of different regions of the H-2 complex were studied with six H-2(b) and three H-2(d) lymphomas induced by five different type C viruses. They were tested in a classical chromium release test against anti-MSV T-killer cells obtained from different inbred strains of mice, including several H-2 recombinants. Tumors o pound the H-2(b) haplotype were lysed only when effectors and target cells have in common the D(b) region. On the contrary an identity limited to the K end of the H-2 complex is necessary and sufficient in the H-2(d) haplotype. An in vitro restimulation of the spleen cells with concanavalin A strongly increased the activity of in vivo-primed T lymphocytes but did not provide any response for in vivo-primed but nonresponder cells. Preincubation of the tumor cells with anti-H-2 sera abolished the lysis by syngeneic anti-MSV effector lymphocytes. The same results were obtained by preincubating the H-2(b) targets with anti-H-2D(b), or the H-2(d) target with anti-H-2K(d). Preincubation with anti-H-2K(b) or anti- H-2D(d) were ineffective. These results show that the T-killer/target cells interaction in the MSV system involved some products of the H-2 complex which might be different with the various H-2 haplotypes and could possibly vary according to the antigenic specificity. A specific association of a viral product with a normal cellular structure, directed by the H-2 region during the viral budding could explain the observed results.

Animals↗

ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics.

BACKGROUND: A disintegrin and metalloprotease 33 (ADAM33) is expressed in the lung by fibroblasts and bronchial smooth muscle cells. Given its structure and cellular provenance, ADAM33 may be associated with airway remodelling and bronchial hyper-responsiveness. Single nucleotide polymorphisms (SNPs) and haplotypes of the ADAM33 gene have previously been associated with asthma susceptibility in the Caucasian population. OBJECTIVE AND METHODS: To assess whether genetic variants of ADAM33 are related to asthma in a Korean population, we conducted an association study of the ADAM33 gene with asthma susceptibility, bronchial hyper-reactivity and serum IgE in Korean asthmatics (n=326) and normal controls (n=151). Five of the 14 polymorphisms originally reported to be associated with asthma development (S1 G>A, T1 T>C, V-1 C>A, V1 T>A, V4 C>G) were genotyped using single base extension and electrophoresis. Haplotypes and their frequencies were inferred using the algorithm implemented by the software Arlequin. Allele frequencies of each SNP and haplotypes were compared between the patients and the normal controls using logistic regression analysis. RESULTS: There was no significant difference in the distribution of SNPs and the six haplotypes between asthmatics and normal controls. All single SNPs and six haplotypes in ADAM33 were also analysed for the association with level of PC(20) using general linear models. The distribution of the T1 T>C SNP and one haplotype (ht4: GCGG) showed significant association with log-transformed PC(20) methacholine level in the asthma patients (P=0.03 and 0.0007, respectively, using a co-dominant model). CONCLUSION: Polymorphism of ADAM33 may contribute to development of BHR in asthma.

ADAM Proteins↗

Glanzmann thrombasthenia. Cooperation between sequence variants in cis during splice site selection.

Glanzmann thrombasthenia (GT), an autosomal recessive bleeding disorder, results from abnormalities in the platelet fibrinogen receptor, GP(IIb)-IIIa (integrin alpha(IIb)beta3). A patient with GT was identified as homozygous for a G-->A mutation 6 bp upstream of the GP(IIIa) exon 9 splice donor site. Patient platelet GP(IIIa) transcripts lacked exon 9 despite normal DNA sequence in all of the cis-acting sequences known to regulate splice site selection. In vitro analysis of transcripts generated from mini-gene constructs demonstrated that exon skipping occurred only when the G-->A mutation was cis to a polymorphism 116 bp upstream, providing precedence that two sequence variations in the same exon which do not alter consensus splice sites and do not generate missense or nonsense mutations, can affect splice site selection. The mutant transcript resulted from utilization of a cryptic splice acceptor site and returned the open reading frame. These data support the hypothesis that pre-mRNA secondary structure and allelic sequence variants can influence splicing and provide new insight into the regulated control of RNA processing. In addition, haplotype analysis suggested that the patient has two identical copies of chromosome 17. Markers studied on three other chromosomes suggested this finding was not due to consanguinity. The restricted phenotype in this patient may provide information regarding the expression of potentially imprinted genes on chromosome 17.

Adult↗

Unexpected high polymorphism at the FABP4 gene unveils a complex history for pig populations.

Fatty acid bing protein 4 (FABP4) plays a key role in fat regulation in mammals and is a strong positional candidate gene for the FAT1 quantitative trait locus located on porcine chromosome 4. DNA resequencing of the FABP4 gene region in 23 pigs from 10 breeds and wild boar revealed 134 variants in 6.4 kb, representing a silent nucleotide diversity of piS=0.01, much higher than reported so far in animal domestic species. Moreover, this diversity was highly structured. Also strikingly, the FABP4 phylogenetic tree did not show any geographical or breed origin clustering, with distant breeds sharing similar haplotypes and some of the most heterozygous samples pertaining to highly inbred animals like Iberian Guadyerbas (inbreeding coefficient approximately 0.3) or British Tamworth. In contrast, the cytochrome b (mtDNA) phylogenetic tree was coherent with geographical origin. The estimated age of the most recent common ancestor for the most divergent Iberian or Tamworth haplotypes was much older than domestication. An additional panel of 100 pigs from 8 different breeds and wild boar from Spain, Tunisia, Sardinia, and Japan was genotyped for seven selected single nucleotide polymorphisms and shows that high variability at the porcine FABP4 is the rule rather than the exception. Pig populations, even highly inbred, can maintain high levels of variability for surprisingly long periods of time.

Animals↗