Ancestral Haplotype Research Articles

A mitochondrial analysis reveals distinct founder effect signatures in Canarian and Balearic goats.

In the course of human migrations, domestic animals often have been translocated to islands with the aim of assuring food availability. These founder events are expected to leave a genetic footprint that may be recognised nowadays. Herewith, we have examined the mitochondrial diversity of goat populations living in the Canarian and Balearic archipelagos. Median-joining network analysis produced very distinct network topologies for these two populations. Indeed, a majority of Canarian goats shared a single ancestral haplotype that segregated in all sampled islands, suggesting a single founder effect followed by a stepping-stone pattern of diffusion. This haplotype also was present in samples collected from archaeological assemblies at Gran Canaria and Lanzarote, making evident its widespread distribution in ancient times. In stark contrast, goats from Majorca and Ibiza did not share any mitochondrial haplotypes, indicating the occurrence of two independent founder events. Furthermore, in Majorcan goats, we detected the segregation of the mitochondrial G haplogroup that has only been identified in goats from Egypt, Iran and Turkey. This finding suggests the translocation of Asian and/or African goats to Majorca, possibly as a consequence of the Phoenician and Carthaginian colonisations of this island.

Informatics resources for the Collaborative Cross and related mouse populations.

Informatics resources for the Collaborative Cross and related mouse populations.

Metageographic population analysis of Colletotrichum truncatum associated with chili fruit rot and other hosts using ITS region nucleotide sequences

Colletotrichum truncatum is one of the most economically important fungal pathogen causing anthracnose disease in pre and post-harvest stages of many crops worldwide. Little information is available in the literature on the genetic analysis and demographic history of this fungal pathogen. In the present study nucleotide sequence data of internal transcribed spacer (ITS) region were analyzed for C. truncatum isolates infecting chili and other crops worldwide to determine a metageographic pattern of distribution and evolution of the species. Levels of differentiation (genetic distances and F ST values) among sequences of C. truncatum from 23 countries were minimal suggesting the global occurrence of a large and geographically undifferentiated population. Only 11 haplotypes were detected among 98 isolates from 24 geographically distant populations of C. truncatum. Predominant haplotype H1 which occupied a central position in the median joining network was inferred to be ancestral haplotype as it was detected at a high frequency and was shared by multiple populations. Phylogeographic pattern of the species with worldwide presence and predominance of single haplotype suggests human mediated dispersal through domestication and introduction of host plants in different parts of the world, and might have played a significant role in structuring the populations of this devastating pathogen.

Morphological and genetic characterization of Sardinian trout Salmo cettii Rafinesque, 1810 and their conservation implications

The morphological and genetic structure of Western Mediterranean trout Salmo cettii inhabiting basins in Sardinia was completed to assist the design of its conservation programmes. Genetic analysis of protein-coding LDH-C1 plus sequencing mitochondrial control region gene and analyses of morphological characters described 253 specimens from seven localities in two basins in Southwest Sardinia. Nuclear and mitochondrial analyses revealed all of the fish were pure-bred native S. cettii, with no introgression from allochthonous S. trutta. The novel 18 mtDNA control region haplotypes were clustered in an ‘insular’ clade, strictly related to the Adriatic haplogroup, and depicted a radial network around two ancestral haplotypes. Completion of discriminant analysis using data on body pigmentation and quantitative morphologic parameters revealed three phenotypic groups within the fish. Each population and phenotype, characterised by high values of nucleotide and haplotype diversity, were not genetically differentiated and not geographically structured according to the two hydrological basins. Geometric morphometric analysis, based on 15 landmarkers, revealed pronounced and highly significant differences in body shape morphology between populations, suggesting S. cettii is locally adapting to extreme environmental conditions and so future management plans for these populations should treat the two basins as distinct morphological units.

Paternal phylogeography and genetic diversity of East Asian goats.

This study was a first analysis of paternal genetic diversity for extensive Asian domestic goats using SRY gene sequences. Sequencing comparison of the SRY 3'-untranslated region among 210 Asian goats revealed four haplotypes (Y1A, Y1B, Y2A and Y2B) derived from four variable sites including a novel substitution detected in this study. In Asian goats, the predominant haplotype was Y1A (62%) and second most common was Y2B (30%). Interestingly, the Y2B was a unique East Asian Y chromosomal variant, which differentiates eastern and western Eurasian goats. The SRY geographic distribution in Myanmar and Cambodia indicated predominant the haplotype Y1A in plains areas and a high frequency of Y2B in mountain areas. The results suggest recent genetic infiltration of modern breeds into South-East Asian goats and an ancestral SRY Y2B haplotype in Asian native goats.

A Mediterranean medicinal plant in the continental Balkans: A plastid DNA-based phylogeographic survey ofSalvia officinalis(Lamiaceae) and its conservation implications

Stojanović D., Aleksić J. M., Jančić I. & Jančić R.: A Mediterranean medicinal plant in the continental Balkans: A plastid DNA-based phylogeographic survey of Salvia officinalis (Lamiaceae) and its conservation implications. — Willdenowia 45: 103–118. 2015. — Version of record first published online on 20 March 2015 ahead of inclusion in April 2015 issue; ISSN 1868-6397; © 2015 BGBM Berlin-Dahlem.DOI: http://dx.doi.org/10.3372/wi.45.45112Salvia officinalis (Lamiaceae), common or Dalmatian sage, is a Mediterranean aromatic and medicinal plant used in medicine since ancient times. Knowledge on current genetic patterns and genealogical history of its natural populations is required for both breeding efforts and species conservation. We used sequences of two chloroplast intergenic spacers, 3′rps16—5′trnK and rpl32—trnL, from 83 individuals from eight natural populations to distinguish between anthropogenic vs natural origin of four disjunct inland populations found outside of the main Adriatic range of the species. We found seven haplotypes, high total gene diversity (HT = 0.695) and genetic differentiation (GST = 0.682), as well as a phylogeographic structure with two lineages, a sub-structured inland-Adriatic lineage (IAL, comprising inland and Adriatic sub-lineages) and a purely Adriatic lineage (PAL). All four inland and disjunct populations, which comprised the inland sub-lineage of IAL, were almost fixed for a distinct haplotype genealogically closely related to the ancestral haplotype and displayed other features of relict populations. Along with previous biogeographic data and other lines of evidence, assumptions on their anthropogenic origin were rejected. At present, a less diverse IAL (Hd = 0.426, π = 0.00106) and a more diverse PAL (Hd = 0.403, π = 0.00257), whose divergence was dated to the Pliocene (3.267 Mya), do not exhibit signs of recent demographic expansions and overlap on the SE Adriatic coast, a region delineated as the main glacial refugium of S. officinalis. Conservation measures accounting for the historical distinctiveness of populations and focusing on currently the most threatened populations are recommended.

Human gephyrin is encompassed within giant functional noncoding yin-yang sequences.

Gephyrin is a highly-conserved gene that is vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis, and other diverse functions. Its specific function is intricately regulated and its aberrant activities have been observed for a number of human diseases. Here we report a remarkable yin-yang haplotype pattern encompassing gephyrin. Yin-yang haplotypes arise when a stretch of DNA evolves to present two disparate forms that bear differing states for nucleotide variations along their lengths. The gephyrin yin-yang pair consists of 284 divergent nucleotide states and both variants vary drastically from their mutual ancestral haplotype, suggesting rapid evolution. Several independent lines of evidence indicate strong positive selection on the region and suggest these high-frequency haplotypes represent two distinct functional mechanisms. This discovery holds potential to deepen our understanding of variable human-specific regulation of gephyrin while providing clues for rapid evolutionary events and allelic migrations buried within human history.

LBP36: MATCHING FOR SNP’S IN THE MHC GAMMA BLOCK REDUCES THE RISK OF GVHD AND INCREASES SURVIVAL RATES POST HSCT

A feature of the MHC is the linkage equilibrium (LD) between alleles of loci that span the MHC. The MHC is usually inherited as a block, resulting in conserved haplotypes (also called Ancestral or Extended Haplotypes) (AH) that have been preserved intact for many generations. Recombination occurs infrequently at specific regions in the MHC creating a genomic block structure with 4 major genomic blocks. Three of these blocks contain commonly typed HLA loci and alleles at these loci serve as markers for their genomic block. The alpha block contains HLA-A, the beta block contains HLA-B and -C and the delta block contains DR and DQ. The Gamma block lies between the beta and delta blocks and contains the complement genes, C2, Bf and C4. These genes are not typed when matching for HSCT, despite being used to characterise AH in the past. Our Gamma-Type test characterises 25 SNP’s within the Gamma block. The majority of these SNPs are in non-coding regions of the Gamma block. Some are AH specific and some are shared between AH. We have shown that HLA mismatched individuals are likely to be Gamma-Type mismatched and HLA matched individuals maybe mismatched or matched. In a recent study of 225 unrelated HSCT, patients who are HLA matched and Gamma-Type matched with their donor had a lower risk of chronic and severe acute GvHD than patients who were HLA matched and Gamma-Type mismatched with their donor. Furthermore HLA mismatched/Gamma-Type matched patients had much greater chances of 5 year survival than HLA mismatched/Gamma-Type mismatched patients. The improved outcomes with Gamma-Type testing probably reflects MHC LD that results in matching the currently unknown MHC loci associated with increased risk of GvHD. The survival outcomes in Gamma-Type matched/HLA mismatched pairs probably reflects the interplay between reducing GvHD (Gamma-Type matching) and reduced likelihood of disease recurrence (HLA mismatching). Both hypotheses require further studies. Gamma-Type is an important test for donor selection in HSCT and mapping disease susceptibility loci in MHC disease gene studies. In addition to testing by PCR-SSP, the Gamma-Type test is also performed by Next Gen sequencing following analysis in our software Assign-MPS, either as a standalone test for retrospective studies or in combination with our Next Gen MPS Resolver HLA assays.

Origin and domestication of papaya Yh chromosome.

Sex in papaya is controlled by a pair of nascent sex chromosomes. Females are XX, and two slightly different Y chromosomes distinguish males (XY) and hermaphrodites (XYh). The hermaphrodite-specific region of the Yh chromosome (HSY) and its X chromosome counterpart were sequenced and analyzed previously. We now report the sequence of the entire male-specific region of the Y (MSY). We used a BAC-by-BAC approach to sequence the MSY and resequence the Y regions of 24 wild males and the Yh regions of 12 cultivated hermaphrodites. The MSY and HSY regions have highly similar gene content and structure, and only 0.4% sequence divergence. The MSY sequences from wild males include three distinct haplotypes, associated with the populations’ geographic locations, but gene flow is detected for other genomic regions. The Yh sequence is highly similar to one Y haplotype (MSY3) found only in wild dioecious populations from the north Pacific region of Costa Rica. The low MSY3-Yh divergence supports the hypothesis that hermaphrodite papaya is a product of human domestication. We estimate that Yh arose only ∼4000 yr ago, well after crop plant domestication in Mesoamerica >6200 yr ago but coinciding with the rise of the Maya civilization. The Yh chromosome has lower nucleotide diversity than the Y, or the genome regions that are not fully sex-linked, consistent with a domestication bottleneck. The identification of the ancestral MSY3 haplotype will expedite investigation of the mutation leading to the domestication of the hermaphrodite Yh chromosome. In turn, this mutation should identify the gene that was affected by the carpel-suppressing mutation that was involved in the evolution of males.

Founder haplotype analysis of Fanconi anemia in the Korean population finds common ancestral haplotypes for a FANCG variant.

A common ancestral haplotype is strongly suggested in the Korean and Japanese patients with Fanconi anemia (FA), because common mutations have been frequently found: c.2546delC and c.3720_3724delAAACA of FANCA; c.307+1G>C, c.1066C>T, and c.1589_1591delATA of FANCG. Our aim in this study was to investigate the origin of these common mutations of FANCA and FANCG. We genotyped 13 FA patients consisting of five FA-A patients and eight FA-G patients from the Korean FA population. Microsatellite markers used for haplotype analysis included four CA repeat markers which are closely linked with FANCA and eight CA repeat markers which are contiguous with FANCG. As a result, Korean FA-A patients carrying c.2546delC or c.3720_3724delAAACA did not share the same haplotypes. However, three unique haplotypes carrying c.307+1G>C, c.1066C > T, or c.1589_1591delATA, that consisted of eight polymorphic loci covering a flanking region were strongly associated with Korean FA-G, consistent with founder haplotypes reported previously in the Japanese FA-G population. Our finding confirmed the common ancestral haplotypes on the origins of the East Asian FA-G patients, which will improve our understanding of the molecular population genetics of FA-G. To the best of our knowledge, this is the first report on the association between disease-linked mutations and common ancestral haplotypes in the Korean FA population.

Haplotypes at LBX1 have distinct inheritance patterns with opposite effects in adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a clinically significant disorder with high heritability that affects 2–4% of the population. Genome-wide association studies have identified LBX1 as a strong susceptibility locus for AIS in Asian and Caucasian populations. Here we further dissect the genetic association with AIS in a Caucasian population. To identify genetic markers associated with AIS we employed a genome-wide association study (GWAS) design comparing 620 female Caucasian patients who developed idiopathic scoliosis during adolescence with 1,287 ethnically matched females who had normal spinal curves by skeletal maturity. The genomic region around LBX1 was imputed and haplotypes investigated for genetic signals under different inheritance models. The strongest signal was identified upstream of LBX1 (rs11190878, Ptrend = 4.18×10-9, OR = 0.63[0.54–0.74]). None of the remaining SNPs pass the genome-wide significance threshold. We found rs11190870, downstream of LBX1 and previously associated with AIS in Asian populations, to be in modest linkage disequilibrium (LD) with rs11190878 (r2 = 0.40, D' = 0.81). Haplotype analysis shows that rs11190870 and rs11190878 track a single risk factor that resides on the ancestral haplotype and is shared across ethnic groups. We identify six haplotypes at the LBX1 locus including two strongly associated haplotypes; a recessive risk haplotype (TTA, Controlfreq = 0.52, P = 1.25×10-9, OR = 1.56), and a co-dominant protective haplotype (CCG, Controlfreq = 0.28, P = 2.75×10-7, OR = 0.65). Together the association signals from LBX1 explain 1.4% of phenotypic variance. Our results identify two clinically relevant haplotypes in the LBX1-region with opposite effects on AIS risk. The study demonstrates the utility of haplotypes over un-phased SNPs for individualized risk assessment by more strongly delineating individuals at risk for AIS without compromising the effect size.

Orientia tsutsugamushi, agent of scrub typhus, displays a single metapopulation with maintenance of ancestral haplotypes throughout continental South East Asia

Orientia tsutsugamushi is the causative agent of scrub typhus, a major cause of febrile illness in rural area of Asia–Pacific region. A multi-locus sequence typing (MLST) analysis was performed on strains isolated from human patients from 3 countries in Southeast Asia: Cambodia, Vietnam and Thailand. The phylogeny of the 56-kDa protein encoding gene was analyzed on the same strains and showed a structured topology with genetically distinct clusters. MLST analysis did not lead to the same conclusion. DNA polymorphism and phylogeny of individual gene loci indicated a significant level of recombination and genetic diversity whereas the ST distribution indicated the presence of isolated patches. No correlation was found with the geographic origin. This work suggests that weak divergence in core genome and ancestral haplotypes are maintained by permanent recombination in mites while the 56-kDa protein gene is diverging in higher speed due to selection by the mammalian immune system.

Allelic variation in the VvMYBA1 and VvMYBA2 domestication genes in natural grapevine populations (Vitis vinifera subsp. sylvestris)

Grape skin color is among the most important qualitative traits on which selection is based in wine and table grape breeding programmes. Skin color is determined by the quantity and composition of anthocyanins. In prior work on cultivated forms, it was shown that polymorphisms in the grape transcription factor family VvMYBA are responsible for anthocyanin content variation in the berries of cultivated grapevine (Vitis vinifera subsp. vinifera). Wild grapevine (V. vinifera subsp. sylvestris) is the ancestor of the cultivated V. vinifera subsp. sativa and has black-colored berries. The purpose of this study was to determine how the VvmybA1 and VvmybA2 polymorphisms emerged and affected the genetic diversity of wild grapevines in the Mediterranean basin by examining samples from the Iberian Peninsula, Italian Peninsula and Caucasian region. Our observations provide evidence that variation in the two transcriptional regulators generated a novel allele series via length polymorphisms in VvmybA1 and a point mutation in VvmybA2, which is lacking in cultivated grapevine. Further, correlation was detected between allele composition and anthocyanin contents. According to polymorphisms in both VvMYBA genes at the color locus, we were able to identify several haplotypes. The most ancestral haplotype (HapN) was found in wild grapevine in the western Mediterranean region and corresponded to wine grape cultivars, whereas recent haplotypes were detected in eastern regions. These eastern zones showed the most diverse haplotypes, which appeared in table cultivars where intense breeding practices may have replaced the original haplotype diversity. These findings provide information about the evolution of grapes since their domestication and have direct implications for wine quality.

A hidden Markov model for investigating recent positive selection through haplotype structure

Recent positive selection can increase the frequency of an advantageous mutant rapidly enough that a relatively long ancestral haplotype will be remained intact around it. We present a hidden Markov model (HMM) to identify such haplotype structures. With HMM identified haplotype structures, a population genetic model for the extent of ancestral haplotypes is then adopted for parameter inference of the selection intensity and the allele age. Simulations show that this method can detect selection under a wide range of conditions and has higher power than the existing frequency spectrum-based method. In addition, it provides good estimate of the selection coefficients and allele ages for strong selection. The method analyzes large data sets in a reasonable amount of running time. This method is applied to HapMap III data for a genome scan, and identifies a list of candidate regions putatively under recent positive selection. It is also applied to several genes known to be under recent positive selection, including the LCT, KITLG and TYRP1 genes in Northern Europeans, and OCA2 in East Asians, to estimate their allele ages and selection coefficients.

A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies.

Jeune asphyxiating thoracic dystrophy (JATD) is a skeletal dysplasia characterized by a small thoracic cage and a range of skeletal and extra-skeletal anomalies. JATD is genetically heterogeneous with at least nine genes identified, all encoding ciliary proteins, hence the classification of JATD as a skeletal ciliopathy. Consistent with the observation that the heterogeneous molecular basis of JATD has not been fully determined yet, we have identified two consanguineous Saudi families segregating JATD who share a single identical ancestral homozygous haplotype among the affected members. Whole-exome sequencing revealed a single novel variant within the disease haplotype in CEP120, which encodes a core centriolar protein. Subsequent targeted sequencing of CEP120 in Saudi and European JATD cohorts identified two additional families with the same missense mutation. Combining the four families in linkage analysis confirmed a significant genome-wide linkage signal at the CEP120 locus. This missense change alters a highly conserved amino acid within CEP120 (p.Ala199Pro). In addition, we show marked reduction of cilia and abnormal number of centrioles in fibroblasts from one affected individual. Inhibition of the CEP120 ortholog in zebrafish produced pleiotropic phenotypes characteristic of cilia defects including abnormal body curvature, hydrocephalus, otolith defects and abnormal renal, head and craniofacial development. We also demonstrate that in CEP120 morphants, cilia are shortened in the neural tube and disorganized in the pronephros. These results are consistent with aberrant CEP120 being implicated in the pathogenesis of JATD and expand the role of centriolar proteins in skeletal ciliopathies.

8q24 risk alleles and prostate cancer in African-Barbadian men.

African American men (AA) exhibit a disproportionate share of prostate cancer (PRCA) incidence, morbidity, and mortality. Several genetic association studies have implicated select 8q24 loci in PRCA risk in AA. The objective of this investigation is to evaluate the association between previously reported 8q24 risk alleles and PRCA in African-Barbadian (AB) men known to have high rates of PRCA. Ten previously reported candidate tag SNPs were genotyped and/or imputed in the 8q24 region in 532 AB men with PRCA and 513 AB controls from the Prostate Cancer in a Black Population (PCBP) study. Rs2124036 was significant in AB men, (OR = 2.7, 95% CI (1.3-5.3), P = 0.005, Empirical (max (T), corrected for multiple testing) P = 0.03) for the homozygous C/C genotype. Only a single SNP from this region remained statistically significant in our analysis of our AB population. These results may indicate the presence of a founder effect or due to the chosen SNPs not tagging an ancestral haplotype bearing the 8q24 risk allele(s) in this population or could reflect inadequate power to detect an association. We conducted a meta-analysis including our AB population along with two additional African Caribbean populations from Tobago and Jamaica for SNPs rs16901979 and rs1447295. Meta-analysis results were most significant for rs16901979 A allele (Z score 2.73; P = 0.006) with a summary OR = 1.31 (95% CI: 1.09-1.58). Additional studies are needed to provide deeper genotype coverage to further interrogate the 8q24 region to understand its contribution to PRCA in this population.

Genetic variability of the invasive snail Pomacea canaliculata in South China based on mitochondrial 16S rDNA sequences

• Species prevalence of Pomacea spp. from 19 regions in South China was identified. • Low genetic variation was not related to geographic distribution patterns of Pomacea canaliculata. • Two haplotypes as the ancestral continental haplotypes of P. canaliculata were found. • Phylogenetic analysis indicated the success invasion of P. canaliculata through secondary introductions in South China.

Parallel genome-wide fixation of ancestral alleles in partially outcrossing experimental populations of Caenorhabditis elegans.

Experimental evolution studies, coupled with new advances in DNA sequencing technology, have become a powerful tool for exploring how populations respond to selection at the genomic level. Recent experiments in microbes typically have found evidence for multiple novel mutations, which are usually fixed. In contrast, in animal model systems, evolutionary responses seem to involve more modest changes in the frequencies of pre-existing alleles, probably because these populations outcross and are usually initialized with greater levels of standing variation. In this experiment, I used whole-genome resequencing to estimate allele frequencies and look for novel substitutions in experimentally evolved populations of Caenorhabditis elegans. These populations were founded with a fixed pair of deleterious mutations introgressed into multiple wild genetic backgrounds and allowed to evolve for 50 generations with a mixed mating system. There is evidence for some recombination between ancestral haplotypes, but selective sweeps seem to have resulted in the fixation of large chromosomal segments throughout most of the genome. In addition, a few new mutations were detected. Simulations suggest that strong selection and low outcrossing rates are likely explanations for the observed outcomes, consistent with earlier work showing large fitness increases in these populations over 50 generations. These results also show clear parallels to population genetic patterns in C. elegans in nature: recent selective sweeps, high linkage disequilibrium, and low effective recombination rates. Thus, the genomic consequences of selection depend heavily on the biology of the organism in question, including its mating system and levels of genetic variation.

Conservation genetics of an endangered cycad, Dioon sonorense (Zamiaceae): implications from variation of chloroplast DNA

The endemic species Dioon sonorense comprises the northernmost group of populations of Dioon , in Sonora, Mexico. Although it is endangered, only the southern populations are protected within a preservation area, while the remaining populations have not been taken into account in management plans or genealogical studies. Describing the intraspecific genealogy and the geographical structure of the genetic variation of D. sonorense may help in the identification of units for further conservation. Therefore, the main objective of this study was to describe the intraspecific genealogy of populations throughout the range of distribution of the endangered species D. sonorense , using haplotypes of the trnL-F spacer of the cpDNA. In addition, the levels of diversity of the employed molecular marker were estimated. Low levels of variability were recorded and at least two evolutionary units, corresponding to each haplotype, were identified as components of the species. The inclusion of northern populations into conservation programs is recommended. In order to integrate these findings to the genealogy of genus Dioon , trnL-F sequences of all the remaining species were merged and analyzed. An ancestral haplotype with wide distribution was detected in several species and one haplotype in D. sonorense was found shared with its sister species, D. tomasellii . This work represents a first attempt to reconcile a genealogical approach in the identification of important centers of genetic diversity of Mexican cycads.

Dating Rare Mutations from Small Samples with Dense Marker Data

We present a method for estimating the age of a mutation based on the genetic length of ancestral haplotypes shared between individuals carrying the mutation. The method can be reliably applied to small samples, typical of situations involving rare mutations, and makes effective use of modern high-density SNP data, thus overcoming two of the limitations with existing methods. The method provides age estimates and confidence intervals without the use of asymptotic theory and is applicable to genealogies in which the data are independent or correlated. In the correlated case we estimate the correlation directly from the data, rather than relying on a model for the genealogy. To demonstrate the method's efficacy, we provide simulation results and compare it to other methods. The length data are obtained with a simple procedure, and an R script is available for performing the calculations.