Ancestral Haplotype Research Articles

Juvenile Dermatomyositis

Juvenile dermatomyositis (JDM) is a rare, presumably autoimmune illness that causes proximal muscle weakness and a variety of typical cutaneous features. The study of this illness has been hampered by its rarity but, in recent years, important developments have increased our understanding of JDM. Genetic factors are likely important in the pathogenesis of JDM. These include several Human Leukocyte Antigen alleles, in particular those associated with the 8.1 ancestral haplotype and the tumor necrosis factor-alpha gene 308 polymorphism. Microchimerism, activation of plasmacytoid dendritic cells, and upregulation of type-1 interferon inducible genes also appear to play an important role in the pathogenesis of JDM. The study of JDM has also been limited by a lack of validated assessment tools. Recent work has validated the Childhood Myositis Assessment Scale and the Childhood Health Assessment Questionnaire as measures of muscle strength and function, and the Cutaneous Assessment Tool as a measure of skin disease activity and damage. Development of core sets of tools that should be used in all JDM studies has also been an important step. The use of magnetic resonance imaging and novel laboratory assessments (such as type-1 interferon inducible gene products, peripheral blood B cell and natural killer cell numbers, and myositis-associated and myositis-specific autoantibodies) are also playing an increasing role in the diagnosis and assessment of JDM. Current treatment is with corticosteroids, frequently in combination with other medications such as methotrexate or intravenous gammaglobulin. Newer therapies, such as anti-tumor necrosis factor agents and rituximab are currently being evaluated; it is not clear what role these medications will have in the future.

Genetic Ancestry, Population Admixture, and the Genetic Epidemiology of Complex Disease

Race/ethnicity is a social construct incorporating biological, sociocultural, psychological, and behavioral components, and there is no genetic definition of race.1 In contrast, genetic ancestry is a genetics concept that describes the architecture of genome variation between populations.2 All genetic variation begins locally, as a new mutation in an individual, and thus, all new mutations are initially geographically localized. By virtue of this shared population history, there is a correlation between genetic variants found in one geographic region as compared with those found elsewhere. It follows that variation that is common across human populations separated by geography tends to be old, and many of these variants were likely present at the time of human expansion out of Africa ≈100 000 years ago.2 In contrast, more recent mutations have not had the time to spread between populations and tend to be of lower frequency, unless under unusual selection pressure and localized to geographic populations. When the recombination history has been short (<20 generations or so), these recent variants will tend to remain in linkage disequilibrium with other markers located on ancestral haplotype on which the new mutation occurs. Article see page 629 Population admixture initially occurred ≈200 years ago because of the African Diaspora.3,4 Since this event, an average of 7 to 10 generations has passed which means that there has been minimal recombination between chromosomes of African and European ancestry. Therefore, population admixture results in long-range linkage disequilibrium between genomic markers segregating along ancestral haplotypes/chromosomal segments. Ancestry informative markers (AIMs) are genetic loci with alleles demonstrating significant frequency differences between populations.5 At the present time, several panels of highly informative AIMs are available to assess admixture between continental populations.6–8 Using a set of genome spanning AIMs and available software packages, each with underlying assumptions regarding …

Shallow phylogeographic structuring of Vimba vimba across Europe suggests two distinct refugia during the last glaciation

Genetic variation and geographical structuring of vimba Vimba vimba were analysed across 26 sites (80 individuals) by means of mtDNA sequences (cyt b gene, mitochondrial control region) to localize hypothesized glacial refugia and to reconstruct postglacial recoloniation routes. Although genetic diversity among sequenced individuals was low, a combined analysis of the two sequenced fragments revealed a western (central and northern Europe: Danube, Elbe and lakes of Sweden) and an eastern clade (eastern Europe: Dnieper-South Bug, Don, Neman). Furthermore, a number of divergent ancestral haplotypes distributed around the Black and Caspian Seas became apparent. Mismatch analyses supported a sudden expansion model for the populations of the western clade between 50 and 10 000 bp. Overall, the study provides strong evidence for a northward and westward expansion of V. vimba from two refugial regions located in the Danubian drainage and the northern Pontic regions respectively.

Population Severance in Manipur at Dopamine Receptor D2 Locus

Tibeto-Burman language-speaking Mongoloid groups of northeast India are reported to be genetically highly heterogeneous. Manipur, one of the states of this region sharing a major International border with Myanmar, is also expected to be diversified as seen by its large number of tribal and nontribal groups. A number of genomic markers, that is, autosomal, mitochondrial, and Y chromosomal ones, have been used to understand the peopling of the northeast region. In this article, an attempt is made to understand the peopling of Manipur using three sites (Taq1A, Taq1B, and Taq1D) on the dopamine receptor D2 (DRD2) gene through allele and haplotype frequencies and their distribution patterns. In total, 367 blood samples were collected from eight populations of which three (Meitei, Muslims, and Bamon) are nontribal groups and five (Aimol, Kabui, Paite, Kom, and Thadou) are tribal groups. All the three sites are polymorphic in all the studied populations with relatively lower heterozyosities indicating a genetic discontinuity between the populations of mainland India and northeast India, suggesting the unlikeliness of eastward migration of people from Africa through India. High heterogeneity and predominance of ancestral haplotype (B2D2A1) among the Meitei suggest an admixture of incoming mongoloid groups with an already existing protoastroloid element. The study also highlights the distinctiveness of Manipuri population groups with respect to DRD2 gene polymorphism.

Haplotype Distribution and Evolutionary Pattern of miR-17 and miR-124 Families Based on Population Analysis

BackgroundMicroRNAs (miRNAs) are small, endogenously expressed non-coding RNAs that regulate mRNAs post-transcriptionally. Previous studies have explored miRNA evolutionary trend, but evolutionary history and pattern in the miRNA world are still not fully clear. In the paper, we intended to analyze miRNA haplotype distribution and evolutionary network by analyzing miRNA sequences of miR-17 and miR-124 families across animal species as special populations.Principal Findings31 haplotypes were detected in miR-17 family while only 9 haplotypes were defined in miR-124 family. The complex miR-17 family was mainly distributed in vertebrates, but miR-124 was shared by more animal species from Caenorhabditis to Homo and had a wide distribution spectrum. Some haplotypes of the two miRNA families appeared discontinuous distributions across animals. Compared with a simple phylogenetic network in miR-124 family, miR-17 family indicated a complex network with some median vectors that might be lost ancestral or potential miRNA haplotypes. By analyzing different miRNAs across 12 animal species, we found these small RNAs showed different haplotype diversities, haplotype distributions and phylogenetic networks.ConclusionsDifferent miRNAs had quite different haplotype distributions and evolutionary patterns. Discontinuous distributions of miRNAs and median vectors in phylogenetic networks implied more members in the miRNA world. miRNA may be an excellent phylogenetic marker to discover its evolutionary history and pattern across the animal kingdom.

Evolution of the VvMybA gene family, the major determinant of berry colour in cultivated grapevine (Vitis vinifera L.)

Polymorphisms in the grape transcription factor family VvMybA are responsible for variation in anthocyanin content in the berries of cultivated grapevine (Vitis vinifera L. subsp. sativa). Previous study has shown that white grapes arose through the mutation of two adjacent genes: a retroelement insertion in VvMybA1 and a single-nucleotide polymorphism mutation in VvMybA2. The purpose of this study was to understand how these mutations emerged and affected genetic diversity at neighbouring sites and how they structured the genetic diversity of cultivated grapevines. We sequenced a total of 3225 bp of these genes in a core collection of genetic resources, and carried out empirical selection tests, phylogenetic- and coalescence-based demographic analyses. The insertion in the VvMybA1 promoter was shown to have occurred recently, after the mutation of VvMybA2, both mutations followed by a selective sweep. The mutational pattern for these colour genes is consistent with progressively relaxed selection from constrained ancestral coloured haplotypes to light coloured and finally white haplotypes. Dynamics of population size in the VvMybA genes showed an initial exponential growth, followed by population size stabilization. Most ancestral haplotypes are found in cultivars from western region, whereas recent haplotypes are essentially present in table cultivars from eastern regions where intense breeding practices may have replaced the original diversity. Finally, the emergence of the white allele was followed by a recent strong exponential growth, showing a very fast diffusion of the initial white allele.

Range shifts of Potentilla fruticosa on the Qinghai-Tibetan Plateau during glacial and interglacial periods revealed by chloroplast DNA sequence variation

The Qinghai-Tibetan Plateau is one of the most extensive habitats for alpine plants in the world. Therefore, the patterns of genetic variation in populations on the Plateau can reveal the detailed demographic history of alpine plants. We analysed the geographical structure of chloroplast matK sequence variation in Potentilla fruticosa L. (Rosaceae), a shrub currently found across the entire Plateau. We obtained sequence data from 508 individuals from 23 populations at sites ranging from the high-altitude interior to the relatively low-altitude northeastern Plateau. In the interior region, genetic diversity was high and included ancestral haplotypes. In contrast, northeastern populations were characterized by relatively low genetic diversity and recently derived haplotypes. The estimated expansion time in the interior population was 17 times that in the northeastern population. These data suggest that P. fruticosa expanded its range on the Plateau during periods of climatic cooling and contracted to the interior region during warmer periods. Thus, the interior region acted as a refugium and greatly contributed to the diversification of P. fruticosa.

Analysis of linkage disequilibrium between the 5′ and 3′ haplotypes of the β-globin gene cluster in Mexican afromestizos

Analysis of the 5′ and 3′ haplotypes (Hps) of the β-globin gene cluster was performed in 110 β A chromosomes from unrelated Mexican afromestizo individuals in order to determine Hardy-Weinberg equilibrium, allelic frequencies, linkage disequilibrium (LD) and association between the 5′ and 3′ haplotypes. All sites were found to be in Hardy–Weinberg equilibrium ( p > 0.05). In the whole β-cluster, only 12.87% of the pairs of loci exhibited significant LD (22/171) ( r 2 > 0.33). Within the 5′Hp, three pairs of loci were associated (ɛ HincII/ Gγ HindIII, ɛ HincII/3′ψβ HincII and Gγ HindIII/3′ψβ HincII). In the 3′Hp, 19 pairs of loci showed significant LD and were distributed mostly among the − 551, − 340, Exon1nt6 and IVS2nt16 polymorphisms. The absence of pairs of loci significantly linked between both 5′ and 3′ Hps is noteworthy. The allelic combinations of the 40 studied polymorphisms (5 sites in the 5′ Hp and 35 sites in the 3′ Hp) displayed 69 distinct haplotypes, 22 of them belonging to group A, 27 to B, 18 to C and 2 to D, which denoted the great heterogeneity of our population. Further, 1a7A1, 1a7B1 and 1a1C1 were the most common sequences with 8, 9 and 9 chromosomes each. Association analysis between both 5′ and 3′ Hps revealed strong coherence with the proposed evolutionary histories for the β-globin gene polymorphisms. 5′Hp1 (+––––), which is considered to be an ancestral haplotype, was the most frequent haplotype found in our population and was linked to 24 different sequences in the 3′Hp, demonstrating great heterogeneity. A similar result was found in the 3′ Hps, where older alleles (a17A1 and a7B1) were linked to a higher number of 5′Hps. This is the first time that an analysis of association among the 5′ and 3′ haplotypes and the LD has been performed with 40 polymorphisms distributed in the β-globin gene cluster in the Mexican afromestizo population. The poor LD observed between and within the 5′ and 3′ Hps show that this region is very prone to recombination events.

An update on the immunogenetics of idiopathic inflammatory myopathies: major histocompatibility complex and beyond

To update the reader on immunogenetic advances in idiopathic inflammatory myopathy (IIM) over the past 18 months. In Caucasian IIM, despite a shared association with the human leukocyte antigen (HLA) 8.1 ancestral haplotype (HLA-DRB1*03-DQA1*05-DQB1*02), anti-Jo-1 and anti-PM-Scl antibody-positive cases have differing IIM clinical phenotypes. A study of the HLA-DPB1 region has shown that DPB1*0101 is associated with anti-Jo-1 positivity but not with anti-PM-Scl. IIM single nucleotide polymorphism studies have demonstrated associations in the protein tyrosine phosphatase, nonreceptor type 22, tumour necrosis factor alpha and interleukin-1 genes. The GM 13 allotype has been confirmed as a risk factor in Caucasian IIM. In inclusion body myositis, the HLA 8.1 ancestral haplotype may not only influence disease susceptibility but also disease expression. A follow-up study including a meta-analysis of the apolipoprotein E gene in inclusion body myositis suggests that this gene does not confer risk of disease. Although a substantial part of the genetic risk for developing adult and juvenile IIM lies within the major histocompatibility complex, recent research suggests that genetic regions outside of the major histocompatibility complex are also potentially involved in conferring IIM disease susceptibility, although with more modest effect sizes. An ongoing and internationally coordinated IIM genome-wide association scan may provide further insights into IIM immunogenetics.

A combined molecular and morphological approach to the taxonomically intricate European mountain plant Papaver alpinum s.l. (Papaveraceae) — taxa or informal phylogeographical groups?

AbstractPapaver alpinum s.l. is an extraordinarily polymorphic taxon distributed throughout southern and central European mountain ranges. We tested previous hypotheses about relationships and taxonomical status of the numerous described taxa within this species or species group by applying different molecular approaches. In addition we re­evaluated morphological characters used in previous taxonomic treatments in the light of the molecular results. The ancestral sequence haplotypes were widespread and dominant throughout the Alps, whereas peripheral populations in other mountain ranges were often characterised by haplotypes directly derived from the central haplotypes involving one or two mutational steps. The AFLP data corroborated the pattern of a 'centrifugal radiation' and additionally showed that most populations were genetically distinct, presumably due to the effect of genetic drift in small and isolated populations. The morphological data did not reveal clear patterns of variation; only the Pyrenean and Sierra Nevada populations differed in two non­overlapping and presumably independent characters. Altogether, our study implies that most previous taxonomic concepts of P. alpinum s. l. were highly artificial, and that either nearly all populations have to be raised to some taxonomic rank or that, preferably, no infraspecific taxa should be recognised at all. The only segregate possibly deserving taxonomic rank, based on both morphology and genetics, is the Iberian P. alpinum subsp. lapeyrousianum.

Refugia within refugia: the case study of a canopy tree (Eurycorymbus cavaleriei) in subtropical China

AbstractAim Eurycorymbus cavaleriei (Lévl.) Rehd. et Hand.‐Mazz. (Sapindaceae) is a Tertiary relict tree endemic to subtropical China. This area is a centre for speciation and evolution within the East Asia biome and one of its most important refugial locations. In this study we aim to elucidate the phylogeographical patterning in E. cavaleriei, in order to identify the locations of the species’ main refugia and the predominant patterns of migration that have led to the contemporary spatial genetic structure of chloroplast variation.Location Subtropical China.Methods We sampled 18 populations of E. cavaleriei throughout its geographical range. Chloroplast DNA (cpDNA) sequence data from two non‐coding regions ((trnS/trnG and pl20/5′‐rps12) were obtained from 170 individuals for phylogeographical analyses. Relationships among cpDNA haplotypes were determined using median‐joining networks. Genetic structure was examined by spatial analysis of molecular variance (SAMOVA). Population differentiation was estimated by GST and NST statistics.Results Ten distinct haplotypes were identified. The level of differentiation among populations was relatively high (GST = 0.817), and NST was significantly higher than GST (P &lt; 0.05), indicating that strong phylogeographical structure is exhibited by this species. The SAMOVA revealed five diverging groups of related haplotypes, which coincide with major landscape features in this region.Main conclusions The high differentiation among populations of E. cavaleriei may be a combined effect of historical and contemporary processes, such as the low effective population size for the chloroplast genome of a dioecious species, long‐term range fragmentation and limited seed dispersal for the species. Clear‐cut geographical distributions of ancestral haplotypes of the species suggest multiple potential refugia across subtropical China. The identified refugial regions have long been recognized as centres of plant diversity and endemism for China and have also been suggested as glacial refugia for many other plant species. The combination of these factors means that these locations should be considered as the highest priority for inclusion in conservation policies and sustainable forest management strategies for subtropical China.

COMPARATIVE PHYLOGEOGRAPHY OF CASTANEA SPECIES

The genus Castanea consists of seven species that are disjunctly distributed in Asia, Europe and North America. Phylogenetic analysis of Castanea using DNA sequence data from six variable regions of the chloroplast genome indicated migration of extant Castanea species from Asia westward to Europe and North America. Cycles of Pleistocene glaciation and environmental events like the spread of chestnut blight were major determinants of historical migration and current genetic diversity in North American Castanea species. Chloroplast and nuclear sequence information revealed two lineages within American chestnut (C. dentata), one which is closely related to Allegheny chinkapin (C. pumila var. pumila) haplotypes from the southern Appalachian region, indicative of hybridization in refuge zones. The other American chestnut lineage expanded in northerly direction following the Last Glacial Maximum, and was accompanied by a gradual loss of diversity. Ozark chinkapins (C. pumila var. ozarkensis) show high sequence homology with the most frequently occurring Allegheny chinkapin haplotype from Virginia and North Carolina. Ancestral Allegheny chinkapin haplotypes can be detected in populations along the Gulf Coast, while haplotypes in Virginia share regions of the chloroplast genome with Ozark and ancestral haplotypes, suggesting multiple colonization routes and suture zones of chloroplast lineages in the Appalachian Mountains. This knowledge will be useful for development of conservation management strategies and successful re-introduction of blight resistant American chestnut into the Appalachian mountain ecosystem.

MtDNA Data Indicate a Single Origin for Dogs South of Yangtze River, Less Than 16,300 Years Ago, from Numerous Wolves

There is no generally accepted picture of where, when, and how the domestic dog originated. Previous studies of mitochondrial DNA (mtDNA) have failed to establish the time and precise place of origin because of lack of phylogenetic resolution in the so far studied control region (CR), and inadequate sampling. We therefore analyzed entire mitochondrial genomes for 169 dogs to obtain maximal phylogenetic resolution and the CR for 1,543 dogs across the Old World for a comprehensive picture of geographical diversity. Hereby, a detailed picture of the origins of the dog can for the first time be suggested. We obtained evidence that the dog has a single origin in time and space and an estimation of the time of origin, number of founders, and approximate region, which also gives potential clues about the human culture involved. The analyses showed that dogs universally share a common homogenous gene pool containing 10 major haplogroups. However, the full range of genetic diversity, all 10 haplogroups, was found only in southeastern Asia south of Yangtze River, and diversity decreased following a gradient across Eurasia, through seven haplogroups in Central China and five in North China and Southwest (SW)Asia, down to only four haplogroups in Europe. The mean sequence distance to ancestral haplotypes indicates an origin 5,400–16,300 years ago (ya) from at least 51 female wolf founders. These results indicate that the domestic dog originated in southern China less than 16,300 ya, from several hundred wolves. The place and time coincide approximately with the origin of rice agriculture, suggesting that the dogs may have originated among sedentary hunter-gatherers or early farmers, and the numerous founders indicate that wolf taming was an important culture trait.

Sporadic inclusion body myositis: HLA-DRB1 allele interactions influence disease risk and clinical phenotype

Susceptibility to sIBM is strongly associated with the HLA-DRB1*03 allele and the 8.1 MHC ancestral haplotype (HLA-A1, B8, DRB1*03) but little is known about the effects of allelic interactions at the DRB1 locus or disease-modifying effects of HLA alleles. HLA-A, B and DRB1 genotyping was performed in 80 Australian sIBM cases and the frequencies of different alleles and allele combinations were compared with those in a group of 190 healthy controls. Genotype–phenotype correlations were also investigated. Amongst carriers of the HLA-DRB1*03 allele, DRB1*03/*01 heterozygotes were over-represented in the sIBM group ( p < 0.003) while. DRB1*03/*04 heterozygotes were under-represented ( p < 0.008). The mean age-at-onset (AAO) was 6.5 years earlier in DRB1*03/*01 heterozygotes who also had more severe quadriceps muscle weakness than the rest of the cohort. The findings indicate that interactions between the HLA-DRB1*03 allele and other alleles at the DRB1 locus can influence disease susceptibility and the clinical phenotype in sIBM.

Genetic composition, population structure and phylogeography of the loggerhead sea turtle: colonization hypothesis for the Brazilian rookeries

The loggerhead sea turtle, Caretta caretta, is the most common species of sea turtle nesting in Brazil and is listed as endangered by the IUCN. Our study characterizes the genetic structure of loggerheads in Brazil based on mitochondrial DNA control region variability and presents a hypothesis for the colonization of Brazilian rookeries. We analyzed 329 samples from Brazilian rookeries and an oceanic foraging ground, and we compared our results with previously published data for other loggerhead populations. Brazilian rookeries had four haplotypes, none of which have been reported for rookeries outside Brazil. Six haplotypes were found in the foraging aggregation. The presence of the CC-A4 haplotype at all sampled sites and the low nucleotide diversity suggest a common origin for all rookeries, with CC-A4 being the ancestral haplotype of the Brazilian populations. The occurrence of three haplotypes in the foraging aggregation that are known only from rookeries outside of Brazil is consistent with the transoceanic migratory behavior of loggerheads. Our results indicated that the colonization of Brazilian rookeries probably occurred from the southern USA stock. This recent colonization most likely followed a north to south route along the Brazilian coastline, influenced by the Brazilian warm current. Our results further suggest the existence of two genetic population units of loggerheads in Brazil and corroborate natal homing behavior in loggerheads.

The origin and evolution of fragrance in rice (Oryza sativa L.).

Fragrance in the grain is one of the most highly valued grain quality traits in rice, yet the origin and evolution of the betaine aldehyde dehydrogenase gene (BADH2) underlying this trait remains unclear. In this study, we identify eight putatively nonfunctional alleles of the BADH2 gene and show that these alleles have distinct geographic and genetic origins. Despite multiple origins of the fragrance trait, a single allele, badh2.1, is the predominant allele in virtually all fragrant rice varieties today, including the widely recognized Basmati and Jasmine types. Haplotype analysis allowed us to establish a single origin of the badh2.1 allele within the Japonica varietal group and demonstrate the introgression of this allele from Japonica to Indica. Basmati-like accessions were nearly identical to the ancestral Japonica haplotype across a 5.3-Mb region flanking BADH2 regardless of their fragrance phenotype, demonstrating a close evolutionary relationship between Basmati varieties and the Japonica gene pool. These results clarify the relationships among fragrant rice varieties and challenge the traditional assumption that the fragrance trait arose in the Indica varietal group.

HLA-DPB1 associations differ between DRB1*03 positive anti-Jo-1 and anti-PM-Scl antibody positive idiopathic inflammatory myopathy

The HLA 8.1 ancestral haplotype (HLA-B*08/DRB1*03/DQA1*05/DQB1*02) is associated with adult/juvenile idiopathic inflammatory myopathy (IIM), but confers a greater strength of association in patients possessing anti-Jo-1 or anti-PM-Scl antibodies. The HLA-DPB1 gene is centromeric to other HLA class II loci and separated by a recombination hotspot. We investigated whether HLA-DPB1 associations differ between anti-Jo-1 and anti-PM-Scl antibody-positive IIM cases. Two hundred and thirty-three adult IIM patients (73% females, 49.4 +/- 13.6 years) with PM (n = 89), DM (n = 88) and myositis associated with another CTD (n = 55) and 85 juvenile DM patients (75% females, 6.2 +/- 3.6 years) were compared with 678 UK Caucasian controls. Patients/controls were genotyped for HLA-DPB1 and DRB1 alleles. Myositis-specific and associated antibodies were identified in cases using immunoprecipitation. HLA-DPB1*0101 was associated with IIM overall [22 vs 13% controls, corrected probability (P(corr)) = 2 x 10(-03); odds ratio (OR) 2.0; 95% CI 1.4, 2.9], PM (P(corr) = 7 x 10(-03); OR 2.5; 95% CI 1.5, 4.4) and anti-Jo-1 (P(corr) = 3 x 10(-5); OR 4.1; 95% CI 2.1, 7.8). No significant DPB1*0101 difference was present between anti-PM-Scl cases and controls. The HLA-DPB1*0101 association in IIM overall cases was dependent on the presence of DRB1*03. A number of HLA-DRB1*03/DPB1 haplotypes were identified, but only DRB1*03/DPB1*0101 was associated with anti-Jo-1 antibody-positive cases. The HLA-DRB1*03/DPB1*0101 haplotype is a risk factor for anti-Jo-1 antibody-positive IIM. Thus, although DRB1*03 is strongly associated with possession of either anti-Jo-1 or anti-PM-Scl, differing antibody associations are observed at the HLA-DPB1 locus.

Role of human leukocyte antigen, killer-cell immunoglobulin-like receptors, and cytokine gene polymorphisms in leptospirosis

Leptospirosis is an emerging zoonotic disease caused by pathogenic species of the genus Leptospira. It has a broad range of clinical presentations in humans. Although progress has been made in the characterization of the host immune system factors that may affect disease progression and outcome, to date few reports have addressed the role of genetic polymorphisms in the susceptibility to leptospirosis. In this work a group of patients with a history of leptospiral infection and a control group were compared for polymorphisms in the human leukocyte antigen (HLA), in killer-cell immunoglobulin-like receptors (KIR), and in cytokine genes. Alleles in the HLA-A and -B loci were associated with susceptibility, as were the class I haplotype A*01-B*08-Cw*07 and the 8.1 ancestral haplotype (A*01-B*08-Cw*07-DRB1*03-DQB1*02). Single nucleotide polymorphisms in the interleukin (IL)-4 and IL-4Rα genes also had significantly higher frequencies in the patient group. No association was reported between KIR gene profile and leptospirosis. This work highlights the importance of using genetic polymorphisms to better understand the mechanisms involved in the immune response to leptospirosis.

Association between Protective and Deleterious HLA Alleles with Multiple Sclerosis in Central East Sardinia

The human leukocyte antigen (HLA) complex on chromosome 6p21 has been unambiguously associated with multiple sclerosis (MS). The complex features of the HLA region, especially its high genic content, extreme polymorphism, and extensive linkage disequilibrium, has prevented to resolve the nature of HLA association in MS. We performed a family based association study on the isolated population of the Nuoro province (Sardinia) to clarify the role of HLA genes in MS. The main stage of our study involved an analysis of the ancestral haplotypes A2Cw7B58DR2DQ1 and A30Cw5B18DR3DQ2. On the basis of a multiplicative model, the effect of the first haplotype is protective with an odds ratio (OR) = 0.27 (95% confidence interval CI 0.13–0.57), while that of the second is deleterious, OR 1.78 (95% CI 1.26–2.50). We found both class I (A, Cw, B) and class II (DR, DQ) loci to have an effect on MS susceptibility, but we saw that they act independently from each other. We also performed an exploratory analysis on a set of 796 SNPs in the same HLA region. Our study supports the claim that Class I and Class II loci act independently on MS susceptibility and this has a biological explanation. Also, the analysis of SNPs suggests that there are other HLA genes involved in MS, but replication is needed. This opens up new perspective on the study of MS.

Inferring Ancestries Efficiently in Admixed Populations with Linkage Disequilibrium

Much effort has recently been invested in developing methods for determining the ancestral origin of chromosomal segments in admixed individuals. Motivations for this task are the study of population history such as bottleneck effects and migration, the assessment of population stratification for adequate adjustment of association studies, and the enhancement of mapping by admixture linkage disequilibrium (MALD). In this article, we present a novel framework for the inference of ancestry at each chromosomal location. The uniqueness of our method stems from the ability to incorporate complex probability models that account for linkage-disequilibrium in the ancestral populations. We provide an inference algorithm that is polynomial in the number of markers even though the underlying problem seems to be inherently exponential in nature. We demonstrate the validity of our model and conclude that, with sufficient ancestral haplotypes, this framework can provide higher accuracy in inferring ancestral origin.