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PubMed2002

SNPSTRs: empirically derived, rapidly typed, autosomal haplotypes for inference of population history and mutational processes.

Each independently evolving segment of the genomes of a sexually reproducing organism has a separate history reflecting part of the evolutionary history of that organism. Uniparentally or clonally inherited DNA segments such as the mitochondrial and chloroplast genomes and the nonrecombining portion of the Y chromosome have provided, to date, most of the known data regarding compound haplotypic variation within and among populations. These comparatively small segments include numerous polymorphic sites and undergo little or no recombination. Recombining autosomes, however, comprise the major repository of genetic variation. Technical challenges and recombination have limited large-scale application of autosomal haplotypes. We have overcome this barrier through development of a general approach to the assessment of short autosomal DNA segments. Each such segment includes one or more single nucleotide polymorphisms (SNPs) and exactly one short tandem repeat (STR) locus. With dramatically different mutation rates, these two types of genetic markers provide complementary evolutionary information. We call the combination of a SNP and a STR polymorphism a SNPSTR, and have developed a simple, rapid method for empirically determining gametic phase for double and triple heterozygotes. Here, we illustrate the approach with two SNPSTR systems. Although even one system provides insight into population history, the power of the approach lies in combining results from multiple SNPSTR systems.

Alleles↗
PubMed2003

Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease.

To date, no dominant mutation has been identified in a significant proportion of patients with type 1 von Willebrand disease (VWD). In this study, we examined 70 families as part of the Canadian Type 1 VWD Study. The entire VWF gene was sequenced for 1 index case, revealing 2 sequence variations: intron 30 (5312-19A>C) and exon 28 at Tyr1584Cys (4751A>G). The Tyr1584Cys variation was identified in 14.3% (10 of 70) of the families and was in phase with the 5312-19A>C variation in 7 (10.0%) families. Both variants were observed in 2 of 10 UK families with type 1 VWD, but neither variant was found in 200 and 100 healthy, unrelated persons, respectively. Mean von Willebrand factor antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo), and factor VIII coagulant activity (FVIII:C) for the index cases in these families are 0.4 U/mL, 0.36 U/mL, and 0.54 U/mL, respectively, and VWF multimer patterns show no qualitative abnormalities. Aberrant VWF splicing was not observed in these patients, and both alleles of the VWF gene are expressed as RNA. Molecular dynamic simulation was performed on a homology model of the VWF-A2 domain containing the Tyr1584Cys mutation. This showed that no significant structural changes occur as a result of the substitution but that a new solvent-exposed reactive thiol group is apparent. Expression studies revealed that the Tyr1584Cys mutation results in increased intracellular retention of the VWF protein. We demonstrate that all the families with the Tyr1584Cys mutation share a common, evolved VWF haplotype, suggesting that this mutation is ancient. This is the first report of a mutation that segregates in a significant proportion of patients with type 1 VWD.

Alleles↗
PubMed2000

Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation.

Interleukin 6 (IL6) plays key roles in hematopoiesis, immune, and acute phase responses. Dysregulated IL6 expression is implicated in diseases such as atherosclerosis and arthritis. We have examined the functional effect of four polymorphisms in the IL6 promoter (-597G-->A, -572G-->C, -373A(n)T(n), -174G-->C) by identifying the naturally occurring haplotypes and comparing their effects on reporter gene expression. The results indicate different transcriptional regulation in the ECV304 cell line compared with the HeLa cell line, suggesting cell type-specific regulation of IL6 expression. The haplotypes showed functional differences in the ECV304 cell line; transcription was higher from the GG9/11G haplotype and lower from the AG8/12G allele. The differences suggest that more than one of the polymorphic sites is functional; the base differences at distinct polymorphic sites do not act independently of one another, and one polymorphism influences the functional effect of variation at other polymorphic sites. These results show that genetic polymorphisms in the promoter influence IL6 transcription not by a simple additive mechanism but rather through complex interactions determined by the haplotype.

Exons↗
PubMed2025

Polaris: Polarization of ancestral and derived polymorphic alleles for inferences of extended haplotype homozygosity in human populations.

SUMMARY: Statistical methods that measure the extent of haplotype homozygosity on chromosomes have been highly informative for identifying episodes of recent selection. For example, the integrated haplotype score (iHS) and the extended haplotype homozygosity (EHH) statistics detect long-range haplotype structure around derived and ancestral alleles indicative of classic and soft selective sweeps, respectively. However, to our knowledge, there are currently no publicly available methods that classify ancestral and derived alleles in genomic datasets for the purpose of quantifying the extent of haplotype homozygosity. Here, we introduce the Polaris package, which polarizes chromosomal variants into ancestral and derived alleles and creates corresponding genetic maps for analysis by selscan and HaploSweep, two versatile haplotype-based programs that perform scans for selection. With the input files generated by Polaris, selscan and/or HaploSweep can produce the appropriate sign (either positive or negative) for outlier iHS statistics, enabling users to distinguish between selection on derived or ancestral alleles. In addition, Polaris can convert the numerical output of these analyses into graphical representations of selective sweeps, increasing the functionality of our software. RESULTS: To demonstrate the utility of our approach, we applied the Polaris package to Chromosome 2 in the European Finnish, Middle Eastern Bedouin, and East African Maasai populations. More specifically, we examined the regulatory sequence in intron 13 of the MCM6 gene associated with lactase persistence (i.e. the ability to digest the lactose sugar present in fresh milk), a region of intense interest to human evolutionary geneticists. Our analyses showed that derived alleles (at known enhancers for lactase expression) sit on an extended haplotype background in the Finnish, Bedouin, and Maasai consistent with a classic selective sweep model as determined by iHS and EHH statistics. Importantly, we were able to immediately identify this target allele under selection based on the information generated by our software. We also explored outlier statistics across Chromosome 2 in two distinct datasets from these populations: (i) one containing polarized alleles generated with Polaris and (ii) the other containing unpolarized alleles in the original phased vcf file. Here, we found an excess of outlier statistics on Chromosome 2 in the unpolarized datasets, raising the possibility that a subset of these "hits" of selection may be unreliable. Overall, Polaris is a versatile package that enables users to efficiently explore, interpret, and report signals of recent selection in genomic datasets. AVAILABILITY AND IMPLEMENTATION: The Polaris package is free and open source on GitHub (https://github.com/alisi1989/Polaris) and DropBox (https://www.dropbox.com/scl/fo/mlxizft5267vem9u62qkn/AAnM0qX923zPzQBlPX8iteM?rlkey=uezrp4t2waffpj0nmo1evr320&e=1&st=jaodccws&dl=0).

Haplotypes↗
PubMedDate not supplied

Semiallogeneic cancer vaccines formulated with granulocyte-macrophage colony-stimulating factor for patients with metastatic gastrointestinal adenocarcinomas: a pilot phase I study.

The authors report the results of a phase I clinical study using semiallogeneic cancer vaccines formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat patients with metastatic adenocarcinomas of the gastrointestinal tract. A specially engineered cell line, FO1-12, was used to generate semiallogeneic hybrids by fusion with patient-derived tumor cells; the hybrids express HLA class I and II haplotypes derived from both parental cells. For treatment, the vaccine was mixed with GM-CSF, irradiated, and injected intradermally into patients at weekly or biweekly intervals. Vaccinations were associated with minimal or no toxicity and showed that semiallogeneic hybrids formulated with GM-CSF can induce a specific antitumor immune response in some patients, as measured by a delayed-type hypersensitivity response to autologous tumor cells. Because of the simplicity, feasibility, and flexibility of this immunotherapeutic approach, semiallogeneic hybrid vaccines have the potential to be used in the treatment of virtually any type of cancer.

Adenocarcinoma↗
PubMed1983

Relation between Friend leukemia virus-induced leukemia and genetic control of the host.

Hematological assays of inbred specific pathogen-free (SPF) mice of ten different strains inoculated with Friend leukemia virus (FLV) were performed chronologically to assess whether the genetic control of the host may play an important role in viral oncogenicity. Mice strains C57BL/6J, B10 (H-2b) and B10D2 (H-2d) were FLV-resistant, BALB/c, DBA/2N (H-2d), RFM (H-2f), AKR and 80% of CBA/JN (H-2k) were FLV-sensitive (polycythemia) and C3H/He, B10Br and 20% of CBA/JN (H-2k) were FLV-sensitive (anemia). Only the AKR strain mice showed a spontaneous regression of splenomegaly. These results indicate that there is not a strong but a weak correlation between the H-2 haplotype and the reaction to FLV. The main phenomenon in the anemic mice was the monotonous proliferation of the naked blastic cell, whereas that in the polycythemic mice was the enormous increase of the mature erythroblast and the decrease of the naked blastic cell in the later phase. These facts suggest that the naked blastic cell in the mice with polycythemia are reactive and that in the mice anemia truly neoplastic.

Anemia↗
PubMed1990

Gametic imprinting and the manifestation of the fused gene in the house mouse.

The phenomenon of gametic imprinting in mammals has raised developmentally relevant questions concerning the manifestation and inheritance of genes with variable penetrance. The dominant fused (Fu) gene located on chromosome 17 is one of the few good cases demonstrating the phenomenon in mice. The Fu mutation has a maternal effect. We have previously shown that the t12 haplotype significantly lowers the penetrance of Fu in female Fu/t12 offspring. Results of reciprocal matings of the heterozygotes for Fu indicated that the Fu of maternal origin has a lowered level of penetrance. The dominant suppressors located outside chromosome 17, in contrast to t12 residing in it, had stronger effects on the manifestation of Fu, decreasing its penetrance to 8-17%. Experimental evidence is presented that the pathway via which Fu passes to the zygote nucleus during gametogenesis through successive generations has a marked effect on its penetrance. Based on this evidence, patterns of genetic imprinting are described. A survey of genetic imprinting allowed us to distinguish two developmental phases, gametic and zygotic. The hypothesis for the gametic phase of the development of multicellular organisms suggests that it proceeds from initialization, a process thought to ensure the freeing of chromosomes from redundant epigenetic information and their preparation for the consecutive developmental cycle.

Animals↗
PubMed1988

Considerations in using linkage analysis as a presymptomatic test for Huntington's disease.

The polymorphic locus D4S10 that is genetically linked to the locus for Huntington's disease (HD) has made possible a presymptomatic test for those at risk. Because the symptoms of this progressively debilitating and fatal illness are not usually manifest until adulthood, the outcome of the test will influence major decisions about career, marriage, and procreation. Several differential diagnoses must be considered before using the test if HD is not confirmed in at least one family member. Review of a large number of pedigrees has shown that 40% of persons at risk do not have appropriate family structure for a linkage test. Furthermore, uncooperative or inaccessible relatives may make this test infeasible for many others who wish to be tested. Linkage phase, which must be known in the affected parent for an informative test, can be determined using one or more of 12 probe-enzyme combinations for D4S10. Although the polymorphism information content (PIC) value for any one RFLP is less than 40%, the PIC value for the haplotype of the two G8 HindIII, pK083 EcoRI, and R7 BglII RFLPs is greater than 88%. We have developed a scheme to incorporate linkage data and age at onset information adjusted for censored observations, sex of affected parent, and familial correlation for age at onset, using the computer program MLINK for calculation of risk of having HD. Simulated experiments showed that proper age at onset adjustment is crucial to the calculation of the probability of risk. A formal presymptomatic testing protocol, including pre- and post-test counselling, psychological testing, and paternity testing is recommended. Many of these considerations are illustrated in several actual test cases.

Adult↗
PubMed1991

Analysis of the expression and immunostimulatory capacity of class I major histocompatibility antigens on rat trophoblast cell lines.

In rat strains expressing the a and other major histocompatibility complex (MHC) haplotypes, subpopulations of placental trophoblast cells synthesize the nonclassical class I Pa antigen in preference to the classical RT1.Aa antigen. In this study, a rat trophoblast cell line, R8RP.3, which was derived from midgestation placentas of PVG.R8 (RT1.Aa) rats, was shown to express class I antigens similarly to those of trophoblast cells in situ. Both unstimulated and IFN-gamma-exposed metabolically labeled R8RP.3 cells synthesized more Pa than RT1.Aa antigen. The reverse was true for labeled spleen cells from PVG.R8 rats. The R8RP.3 cells failed to stimulate allogeneic lymphocyte proliferation even when high levels of both classical and nonclassical class I MHC antigens were expressed on their membranes after incubation with IFN-gamma. These experiments thus supply the first evidence that the inductive phase of the immune response is not promoted by trophoblast cell class I MHC antigens, which could explain the failure of mothers to mount immune responses to class I MHC positive trophoblast cells.

Animals↗
PubMed1996

Mannose-binding protein genetic polymorphisms in black patients with systemic lupus erythematosus.

OBJECTIVE: To determine whether dysfunctional or deficient mannose-binding protein (MBP) variants are found with increased frequency in black patients with systemic lupus erythematosus (SLE) compared with controls. METHODS: Allele-specific polymerase chain reaction amplification of 4 different polymorphic sites was performed on samples from 92 black SLE patients and 86 geographically matched black controls. RESULTS: Two structural polymorphisms of MBP, associated with low serum levels of MBP, were found with significantly increased frequency in the SLE patient population compared with controls. In contrast, a promoter haplotype associated with particularly high serum levels of MBP was negatively associated with SLE. CONCLUSION: Deficiencies of MBP predispose individuals to SLE.

Acute-Phase Proteins↗
PubMed2005

Tumor development: haploinsufficiency and local network assembly.

According to the current models, tumor development is a continuous process of mutation accumulation, leading to several intermediate phenotypes and final phases of autonomy, unlimited growth and metastasis. One of the most important events in that process is the initial destabilization of cellular pathways that subsequently allow mutations to accumulate. The mechanisms involved in that stage are not clear. In principle, the estimated very low mutation frequency in human or mouse cells would suggest that accumulating the required number of mutations for tumor development should be a statistically unlikely event. However, this theory is contradicted by the high incidence of cancers. Here we discuss the role of protein haploinsufficiency as a contributor to the initial phases of tumor development, and suggest possible mechanisms that might be involved in that process.

Animals↗
PubMed2002

Re-sequencing of multiple single nucleotide polymorphisms by liquid chromatography-electrospray ionization mass spectrometry.

Allelic discrimination of single nucleotide polymorphisms (SNPs) and, particularly, determination of the phase of multiple variations are of utmost importance in genetics. The physicochemical separation of alleles by completely denaturing ion-pair reversed-phase high-performance liquid chromatography and their on-line sequence determination by electrospray ionization mass spectrometry is demonstrated. Simultaneous genotyping of two and three simple sequence polymorphisms contained within 73-114 bp was accomplished with low femtomolar amounts of unpurified amplicons from polymerase chain reaction. Determination of allelic composition is enabled by the high accuracy (better than 0.019%) of intact mass measurements or by comparative sequencing using gas-phase fragmentation and tandem mass spectrometry in combination with fully automated, computer-aided data interpretation.

Chromatography, Liquid↗
PubMed2026

The Rise of Plant Pan-Genomes: From Genome Variation to Predictive Breeding.

Plant pan-genomics is entering a new phase beyond genome variation discovery, requiring a shift from cataloguing genomic diversity toward understanding how variation generates biological function and breeding value. Here, we propose that the future of plant pan-genomics will be shaped by three conceptual transitions. First, structural variation (SV), presence-absence variation (PAV), and haplotype diversity should be interpreted not merely as genomic differences, but as regulatory components that influence gene networks, chromatin organization, and complex traits. Second, the expansion from species-level pan-genomes to genus-level super pan-genomes provides an evolutionary framework for uncovering adaptive genetic modules preserved in wild relatives and overlooked during domestication. Third, integrating pan-genomes with pan-omics, three-dimensional genome analyses, and artificial intelligence will enable the transformation of genomic variation into predictive models for crop improvement. We further propose that the ultimate value of pan-genomes lies not in generating increasingly complete genome collections, but in establishing a mechanistic bridge between genome diversity, biological function, and breeding decisions. This transition will move crop improvement from empirical selection toward rational genome design, where evolutionary diversity can be systematically interpreted, predicted, and engineered.

Journal Article↗
PubMed2001

COL4A4 mutation in thin basement membrane disease previously described in Alport syndrome.

BACKGROUND: Carriers of autosomal-recessive and X-linked Alport syndrome often have a thinned glomerular basement membrane (GBM) and have mutations in the COL4A3/COL4A4 and COL4A5 genes respectively. Recently, we have shown that many individuals with thin basement membrane disease (TBMD) are also from families where hematuria segregates with the COL4A3/COL4A4 locus. This study describes the first COL4A4 mutation in an individual with biopsy-proven TBMD who did not have a family member with autosomal-recessive or X-linked Alport syndrome, inherited renal failure, or deafness. METHODS: The index case and all available family members were examined for dysmorphic hematuria> 50,000/mL using phase contrast microscopy and for segregation of hematuria with the COL4A3/COL4A4 and COL4A5 loci using DNA satellite markers. COL4A4 exons from the index case were then studied using the enzyme mismatch cleavage method, and exons that demonstrated abnormal cleavage products were sequenced. RESULTS: Hematuria in this family segregated with a haplotype at the COL4A3/COL4A4 locus (P = 0.031) but not with haplotypes at the COL4A5 locus. A mutation in COL4A4 that changed C to T resulting in an arginine residue being replaced by a stop codon (R1377X) was demonstrated in exon 44, which encodes part of the alpha 4(IV) collagen sequence close to the junction with the noncollagenous domain. This mutation was present in all five family members with hematuria, but not in the four unaffected family members, 33 unrelated individuals with TBMD, or 22 nonhematuric normals. CONCLUSIONS: R1377X has been described previously in a compound heterozygous form of autosomal-recessive Alport syndrome. Our observation is evidence that TBMD can represent a carrier state for autosomal-recessive Alport syndrome in at least some individuals.

Basement Membrane↗
PubMed2004

Hb Yaoundé [beta134(H12)Val-->Ala] in association with Hb C [beta6(A3)Glu-->Lys] in a Caucasian Portuguese family.

Hb Yaoundé [beta134(H12)Val-->Ala] is a rare, silent and asymptomatic hemoglobin (Hb) variant. It was previously reported in a Black man from Cameroon, in association with Hb Kenitra [beta69(E13)Gly-->Arg], and was subsequently found and described as Hb Mataro in a sub-Saharan child. To date, Hb Yaoundé has not been described in Caucasian people and molecular studies have never been performed. Here we describe a three-generation Caucasian Portuguese family in whom Hb Yaoundé was found in association with Hb C [beta6(A3)Glu-->Lys] (in the proband) and in a heterozygous state (in the proband's mother). The Hb studies of the proband's hemolysate, performed by isoelectric focusing (IEF) and low-pressure cation exchange chromatography, only revealed an Hb variant identified as Hb C by comparison with a control. However, analysis performed by reversed-phase high-performance liquid chromatography (HPLC) showed two different beta chain variants and a complete absence of the normal beta chain. This uncommon Hb variant was identified as Hb Yaoundé by DNA sequencing analysis of the beta-globin gene (codon 134, GTG-->GCG). The beta-globin gene haplotypes were determined in all family members using polymerase chain reaction (PCR)-based methodology; Hb Yaoundé was found to be associated with the Mediterranean haplotype II. This study is the first description of Hb Yaoundé in Caucasian individuals, and its association with a Mediterranean haplotype supports the hypothesis of an independent genetic origin other than African.

Chromatography, Ion Exchange↗
PubMed2006

Low-cost, simultaneous, single-sequence genotyping of the HLA-A, HLA-B and HLA-C loci.

New automated DNA sequencing technology has enabled the development of an assay for genotyping the three major HLA class 1 loci from a single sequence of each gene containing exon 3, intron 2 and exon 2. The assay allows 31 subjects (with 3 negative controls) to be genotyped at all three loci simultaneously, using a 96-well plate format. Genotypes were assigned by comparing each sequence to a database of 307 HLA-A, 563 HLA-B and 166 HLA-C alleles. Unequivocal, 4-digit allele assignments were made for 40 of 130 HLA-A genes, 82 of 130 HLA-B genes and 97 of 130 HLA-C genes from 21 European, 20 Tongan and 24 Niuean subjects. Ambiguity in interpretation of the sequence contributed to 66 of the 170 equivocal allele assignments, and 105 equivocal assignments were due to polymorphisms outside exons 2 and 3. All known alternative interpretations of ambiguous genotypes were identified, and seven HLA-B and two HLA-C ambiguities were resolved by reading the out-of-phase exon 2 sequence that followed an indel in intron 2. The genotypes of a subgroup of 27 heterozygous subjects, whose genotypes contained all of the alleles identified in this study, were confirmed with commercial, generic PCR-SSP typing. In European subjects, the repertoire of HLA-B/HLA-C haplotypes was almost identical to previously published data. We identified five new HLA-B/HLA-C haplotypes in the Polynesian subjects, and the remaining haplotypes were of Asian origin. In summary, we are describing a low-cost, sequencing assay for the three major HLA class I loci that provides a level of resolution that is comparable with a commercial PCR-SSP assay.

Alleles↗
PubMed2005

The 3p21.1-p21.3 hereditary vascular retinopathy locus increases the risk for Raynaud's phenomenon and migraine.

Previously, we described a large Dutch family with hereditary vascular retinopathy (HVR), Raynaud's phenomenon and migraine. A locus for HVR was mapped on chromosome 3p21.1-p21.3, but the gene has not yet been identified. The fact that all three disorders share a vascular aetiology prompted us to study whether the HVR haplotype also contributed to Raynaud's phenomenon and migraine in this family. Whereas the parent-child transmission disequilibrium test (TDT) did not reach significance, the sibling TDT revealed that the HVR haplotype harbours a susceptibility factor for Raynaud's phenomenon and migraine. Identification of the HVR gene will improve the understanding of the pathophysiology of HVR, Raynaud's phenomenon and migraine.

Adolescent↗
PubMed2024

Phased telomere-to-telomere reference genome and pangenome reveal an expansion of resistance genes during apple domestication.

The cultivated apple (Malus domestica Borkh.) is a cross-pollinated perennial fruit tree of great economic importance. Earlier versions of apple reference genomes were unphased, fragmented, and lacked comprehensive insights into the apple's highly heterozygous genome, which impeded advances in genetic studies and breeding programs. In this study, we assembled a haplotype-resolved telomere-to-telomere (T2T) reference genome for the diploid apple cultivar Golden Delicious. Subsequently, we constructed a pangenome based on 12 assemblies from wild and cultivated species to investigate the dynamic changes of functional genes. Our results revealed the gene gain and loss events during apple domestication. Compared with cultivated species, more gene families in wild species were significantly enriched in oxidative phosphorylation, pentose metabolic process, responses to salt, and abscisic acid biosynthesis process. Our analyses also demonstrated a higher prevalence of different types of resistance gene analogs (RGAs) in cultivars than their wild relatives, partially attributed to segmental and tandem duplication events in certain RGAs classes. Structural variations, mainly deletions and insertions, have affected the presence and absence of TIR-NB-ARC-LRR, NB-ARC-LRR, and CC-NB-ARC-LRR genes. Additionally, hybridization/introgression from wild species has also contributed to the expansion of resistance genes in domesticated apples. Our haplotype-resolved T2T genome and pangenome provide important resources for genetic studies of apples, emphasizing the need to study the evolutionary mechanisms of resistance genes in apple breeding.

Malus↗