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PubMed2025

Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.

Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.

Leukemia, Myeloid, Acute↗
PubMed1990

Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B100.

Haplotype analysis was conducted on the mutant allele of 14 unrelated subjects heterozygous for a mutation in the codon for amino acid 3500 of human apolipoprotein B100. This mutation is associated with defective binding of low-density lipoprotein to the low-density lipoprotein receptor and with moderate hypercholesterolemia. Ten markers were used for haplotyping: eight diallelic markers within the structural gene and two hypervariable loci flanking the gene. Seven of eight unequivocally deduced haplotypes were identical, and one revealed only a minor difference at one of the hypervariable loci. The genotypes of the six other affected subjects were consistent with this same assigned haplotype. These data are consistent with a common ancestral chromosome and provide no evidence for a recurrent mutation at this potentially hypermutable CG dinucleotide, despite the fact that this mutation is not rare.

Alleles↗
PubMed2006

Molecular epidemiology of hereditary epidermolysis bullosa in a Middle Eastern population.

Epidermolysis bullosa (EB) encompasses a large group of inherited blistering skin disorders caused by mutations in at least 10 genes. Numerous studies, mainly performed in European and US families with EB, have revealed a number of characteristic epidemiological and genetic features, which form the basis for current diagnostic and counseling strategies. However, little is currently known about the molecular epidemiology of EB in Middle East populations. In the present study, we assessed 55 EB families for pathogenic sequence alterations in the 10 genes known to be associated with EB. Our results show unique EB subtype distribution and patterns of inheritance in our cohort. We also failed to detect recurrent mutations frequently encountered in Europe and the US, and did not consistently observe genotype-phenotype correlations formerly established in Western populations. Thus, the molecular epidemiology of EB in the Middle East is significantly different from that previously delineated in Europe and the US. Our data raise the possibility that similar differences may also be found in other genetically heterogeneous groups of disorders, and indicate the need for population-specific diagnostic and management approaches.

Asian People↗
PubMed2002

Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype.

PEX7 encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Mutations in PEX7 cause rhizomelic chondrodysplasia punctata (RCDP), a distinct peroxisome biogenesis disorder. In previous work we described three novel PEX7 mutant alleles, including one, L292X, with a high frequency due to a founder effect. We have now extended our analysis to 60 RCDP probands and identified a total of 24 PEX7 alleles, accounting for 95% of the mutant PEX7 genes in our sample. Of these, 50% are L292X, 13% are IVS9+1G>C, and the remainder are mostly private. IVS9+1G>C occurs on at least three different haplotypes and thus appears to result from recurrent mutation. The phenotypic spectrum of RCDP is broader than commonly recognized and includes minimally affected individuals at the mild end of the spectrum. To relate PEX7 genotype and phenotype, we evaluated the consequence of the disease mutation on PEX7 RNA by Northern analysis and RT/PCR. We evaluated the function of the encoded Pex7 protein (Pex7p) by expressing selected alleles in fibroblasts from RCDP patients and assaying their ability to restore import of a PTS2 marker protein. We find that residual activity of mutant Pex7p and reduced amounts of normal Pex7p are associated with milder and variant phenotypes.

Adolescent↗
PubMed2000

Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus.

The Duffy blood group locus, which encodes a chemokine receptor, is characterized by three alleles-FY*A, FY*B, and FY*O. The frequency of the FY*O allele, which corresponds to the absence of Fy antigen on red blood cells, is at or near fixation in most sub-Saharan African populations but is very rare outside Africa. The FST value for the FY*O allele is the highest observed for any allele in humans, providing strong evidence for the action of natural selection at this locus. Homozygosity for the FY*O allele confers complete resistance to vivax malaria, suggesting that this allele has been the target of selection by Plasmodium vivax or some other infectious agent. To characterize the signature of directional selection at this locus, we surveyed DNA sequence variation, both in a 1.9-kb region centered on the FY*O mutation site and in a 1-kb region 5-6 kb away from it, in 17 Italians and in a total of 24 individuals from five sub-Saharan African populations. The level of variation across both regions is two- to threefold lower in the Africans than in the Italians. As a result, the pooled African sample shows a significant departure from the neutral expectation for the number of segregating sites, whereas the Italian sample does not. The FY*O allele occurs on two major haplotypes in three of the five African populations. This finding could be due to recombination, recurrent mutation, population structure, and/or mutation accumulation and drift. Although we are unable to distinguish among these alternative hypotheses, it is likely that the two major haplotypes originated prior to selection on the FY*O mutation.

Africa South of the Sahara↗
PubMed2005

The rat pink-eyed dilution (p) mutation: an identical intragenic deletion in pink-eye dilute-coat strains and several Wistar-derived albino strains.

We identified the rat pink-eyed dilution (p) and pink eye Mishima (p(m)) mutations. The p(m) mutation, which was isolated from a wild rat caught in Mishima Japan in 1961 and is carried in the NIG-III strain, is a splice donor site mutation in intron 5. The p mutation, which was first described in 1914 and is carried in several p/p rats including the RCS and BDV strains, is an intragenic deletion including exons 17 and 18. In addition to RCS and BDV strains, several albino strains, KHR, KMI and WNA, all descendants of albino stock of the Wistar Institute, are homozygous for the p allele. Analyses revealed that the colored p strains and the Wistar-derived albino p strains had the same marker haplotype spanning approximately 4 Mb around the P locus. This indicates that these p strains share a common ancestor and the p allele did not arise independently via recurrent mutations. The historical relationship among the p strains suggests that the p deletion had been maintained in stock heterogeneous for the C and P loci and then was inherited independently by the ancestor of the Wistar albino stock and the ancestor of the pink-eyed agouti rats in Europe.

Albinism↗
PubMed2004

DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese.

Glycogen storage disease type III (GSD III) is an inborn error of glycogen metabolism caused by a deficiency of glycogen debranching enzyme (AGL). Here, we investigate two unrelated Hong Kong Chinese GSD III patients and identify a novel 5-base pair deletional mutation, 2715_2719delTCAGAin exon 22, in one patient and a nonsense mutation, 1222C>T (R408X) in exon 11, in another patient. Since GSD IIIb is only caused by mutation in exon 3 of the AGL gene, we diagnose our patients to have GSD IIIa, which is consistent with the clinical diagnosis. Until now, R408X has only been reported in Faroe Islands GSDIII patients and was thought to demonstrate a founder effect. In this study, haplotyping of the disease-bearing chromosomes in the AGL locus by 19 intragenic single nucleotide polymorphisms shows that R408X is linked with IVS16+8T and IVS23-21T in our patient while R408X is linked with IVS16+8C and IVS23-21A in the Faroe Islands. The different haplotypes of R408X in Chinese and Faroese indicated that R408X is a recurrent mutation.

Asian People↗
PubMed1997

Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses.

New mutations for Huntington disease (HD) arise from intermediate alleles (IAs) with between 29 and 35 CAG repeats that expand on transmission through the paternal germline to 36 CAGs or greater. Using single sperm analysis, we have assessed CAG mutation frequencies for four IAs in families with sporadic HD (IANM) and IAs ascertained from the general population (IAGP) by analyzing 1161 single sperm from three persons. We show that IANM are more unstable than IAGP with identical size and sequence. Furthermore, comparison of different sized IAs and IAs with different sequences between the CAG and the adjacent CCG tracts indicates that DNA sequence is a major influence on CAG stability. These studies provide estimates of the likelihood of expansion of IANM and IAGP to > or = 36 CAG repeats for these individuals. For an IA with a CAG of 35 in this family with sporadic HD, the likelihood for siblings to inherit a recurrent mutation > or = 36 CAG is approximately 10%. For IAGP of a similar size, the risk of inheriting an expanded allele of > or = 36 CAG through the paternal germline is approximately 6%. These risk estimates are higher than previously reported and provide additional information for counselling in these families. Further studies on persons with IAs will be needed to determine whether these results can be generalized to other families.

Alleles↗
PubMed2005

Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management.

PURPOSE: To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals. EXPERIMENTAL DESIGN: We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing. RESULTS: We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers. CONCLUSIONS: In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

Adult↗
PubMedDate not supplied

Molecular heterogeneity of G6PD deficiency in an Amazonian population and description of four new variants.

To characterize the molecular variation in the glucose-6-phosphate dehydrogenase gene (G6PD), 196 asymptomatic and unrelated male G6PD-deficient blood donors from Belém, an Amazonian metropolis (Brazil), were analyzed. This deficiency was detected by horizontal agarose gel electrophoresis and quantitative spectrophotometric assay for enzyme activity. The mutations were searched by PCR/RFLP, SSCP, and direct DNA sequencing. The most frequent G6PD variant was the widespread and common G6PD A- (202G --> A, 376A --> G) observed in 161 subjects (82.1%). Besides this, we found another form of G6PD A- (968T --> C, 376A --> G) in 14 (7.1%) individuals, G6PD Seattle (844G --> C) in 4.6%, G6PD Santamaria (542A --> T, 376A --> G) in 2.5%, and G6PD Tokyo (1246G --> A) in one blood donor. Four novel variants were also identified: G6PD Belém (409C --> T; Pro137His), G6PD Ananindeua (376A --> G, 871G --> A; Asn126Asp, Val291Met), G6PD Crispim with four point mutations (375G --> T, 379G --> T, 383T --> C, and 384C --> T) leading to three amino acid substitutions (Met125Ile, Ala127Ser, and Leu128Pro), and G6PD Amazonia (185C --> A; Pro62His). The reported frequencies do not reflect the real values for blood donors from Belém, since an excess of individuals with "non A-" phenotype was included in this study to enhance the probability to find rare variants. Haplotype analyses were carried out for the less common G6PD variants identified in our study using PCR/RFLP for five polymorphic sites (FokI, PvuII, PstI, BclI, NlaIII). G6PD Crispim and G6PD Amazonia variants presented the most common haplotype found in G6PD B (- - + - -). G6PD Belém presented two haplotypes (- - + + +, - + + + +) and G6PD Ananindeua was found with the + - + - + haplotype. The reported heterogeneity probably is due to the great miscegenation, characteristic of the population of the Amazonian region, besides the apparently common occurrence of recurrent mutations in the G6PD gene.

Amino Acid Substitution↗
PubMed1999

BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations.

PURPOSE: Breast cancer patients treated conservatively with lumpectomy and radiation therapy (LRT) have an estimated lifetime risk of local relapse (ipsilateral breast tumor recurrence [IBTR]) of 10% to 15%. For breast cancer patients carrying BRCA1 or BRCA2 (BRCA1/2) mutations, the outcome of treatment with LRT with respect to IBTR has not been determined. In this study, we estimate the frequency of BRCA1/2 mutations in a study of breast cancer patients with IBTR treated with LRT. PATIENTS AND METHODS: Between 1973 and 1994, there were 52 breast cancer patients treated with LRT who developed an IBTR within the prior irradiated breast and who were willing to participate in the current study. From our database, we also identified 52 control breast cancer patients treated with LRT without IBTR. The control patients were individually matched to the index cases with respect to multiple clinical and pathologic parameters. Lymphocyte DNA specimens from all 52 locally recurrent patients and 15 of the matched control patients under age 40 were used as templates for polymerase chain reaction amplification and dye-primer sequencing of exons 2 to 24 of BRCA1, exons 2 to 27 of BRCA2, and flanking intron sequences. RESULTS: After LRT, eight (15%) of 52 breast cancer patients had IBTR with deleterious BRCA1/2 mutations. By age, there were six (40%) of 15 patients with IBTR under age 40 with BRCA1/2 mutations, one (9.0%) of 11 between ages 40 and 49, and one (3.8%) of 26 older than age 49. In comparison to the six (40%) of 15 of patients under age 40 with IBTR found to have BRCA1/2 mutations, only one (6.6%) of 15 matched control patients without IBTR and had a BRCA1/2 mutation (P =.03). The median time to IBTR for patients with BRCA1/2 mutations was 7.8 years compared with 4.7 years for patients without BRCA1/2 mutations (P =.03). By clinical and histologic criteria, these relapses represented second primary tumors developing in the conservatively treated breast. All patients with BRCA1/2 mutations and IBTR underwent successful surgical salvage mastectomy at the time of IBTR and remain alive without evidence of local or systemic progression of disease. CONCLUSION: In this study, we found an elevated frequency of deleterious BRCA1/2 mutations in breast cancer patients treated with LRT who developed late IBTR. The relatively long time to IBTR, as well as the histologic and clinical criteria, suggests that these recurrent cancers actually represent new primary breast cancers. Early onset breast cancer patients experiencing IBTR have a disproportionately high frequency of deleterious BRCA1/2 mutations. This information may be helpful in guiding management in BRCA1 or BRCA2 patients considering breast-conserving therapy.

Adult↗
PubMed2005

Population genetics of microbial pathogens estimated from multilocus sequence typing (MLST) data.

The inference of population recombination (rho), population mutation (Theta), and adaptive selection is of great interest in microbial population genetics. These parameters can be efficiently estimated using explicit statistical frameworks (evolutionary models) that describe their effect on gene sequences. Within this framework, we estimated rho and Theta using a coalescent approach, and adaptive (or destabilizing) selection under heterogeneous codon-based and amino acid property models in microbial sequences from MLST databases. We analyzed a total of 91 different housekeeping gene regions (loci) corresponding to one fungal and sixteen bacterial pathogens. Our results show that these three population parameters vary extensively across species and loci, but they do not seem to be correlated. For the most part, estimated recombination rates among species agree well with previous studies. Over all taxa, the rho/Theta ratio suggests that each factor contributes similarly to the emergence of variant alleles. Comparisons of Theta estimated under finite- and infinite-site models indicate that recurrent mutation (i.e., multiple mutations at some sites) can increase Theta by up to 39%. Significant evidence of molecular adaptation was detected in 28 loci from 13 pathogens. Three of these loci showed concordant patterns of adaptive selection in two to four different species.

Alleles↗
PubMed2000

Phylogenetic network of the mtDNA haplogroup U in Northern Finland based on sequence analysis of the complete coding region by conformation-sensitive gel electrophoresis.

Mutations in mtDNA have accumulated sequentially, and maternal lineages have diverged to form population-specific genotypes. Classification of the genotypes has been made based on differences found in restriction fragment analysis of the coding region or in the sequence of the hypervariable segment I. Both methods have shortcomings, as the former may not detect all the important polymorphisms and the latter makes use of a segment containing hypervariable nucleotide positions. Here, we have used conformation-sensitive gel electrophoresis (CSGE) to detect polymorphisms within the coding region of mtDNA from 22 Finns belonging to haplogroup U. Sixty-three overlapping PCR fragments covering the entire coding region were analyzed by CSGE, and the fragments that differed in their migration pattern were sequenced. CSGE proved to be a sensitive and specific method for identifying mtDNA substitutions. The phylogenetic network of the 22 coding-region sequences constituted a perfect tree, free of homoplasy, and provided several previously unidentified common polymorphisms characterizing subgroups of U. After contrasting this data with that of hypervariable segment I, we concluded that position 16192 seems to be prone to recurrent mutations and that position 16270 has experienced a back mutation. Interestingly, all 22 samples were found to belong to subcluster U5, suggesting that this subcluster is more frequent in Finns than in other European populations. Complete sequence data of the mtDNA yield a more reliable phylogenetic network and a more accurate classification of the haplogroups than previous ones. In medical genetics, such networks may help to decide between a rare polymorphism and a pathogenic mutation; in population genetics, the networks may enable more detailed analyses of population history and mtDNA evolution.

Codon↗
PubMed1984

Adaptation of insects to insecticides.

Insects have successfully adapted to most insecticides by becoming resistant to them. This adaptation, of recent origin, has evolved rapidly and independently in a large number of species and is of serious economic and medical importance. The origins of resistance are still obscure, but resistance is assumed to be pre-adaptive, arising through recurrent mutation of existing alleles. However, in at least one well-researched case it probably originated by gene duplication. Resistance can be monofactorial or multifactorial. When several independent mechanisms confer resistance to the same group of insecticides the order in which these mechanisms are selected may reflect their effectiveness in protecting insects from the toxic effects of the different compounds. Our concept of resistance is changing as insects continue to adapt to the insecticide-containing environment. Criteria for defining resistance in both fundamental and practical terms are re-examined here in the light of recent work.

Adaptation, Biological↗
PubMed1995

Increased microsatellite variability in Macaca mulatta compared to humans due to a large scale deletion/insertion event during primate evolution.

Human (GATA)n microsatellites D12S66 and D12S67 could be successfully amplified by polymerase chain reaction (PCR) in various species of apes and monkeys. In 86 unrelated animals of the most intensively studied species Macaca mulatta we demonstrated five alleles at "D12D66" differing in size in increments of 4 bp (159-175 bp), whereas 17 alleles were observed at locus "D12S67". The alleles of the latter locus are distributed in two separate groups with no alleles of intermediate size. Six alleles were found between 108-128 bp and 11 alleles between 181-249 bp. Mendelian inheritance of the codominant allele was proven by family studies. Sequencing of the "D12S67" locus revealed that the shorter alleles are characterized by a single perfect (GATA)n stretch whereas the longer alleles consist of two blocks of (GATA)n repeats separated by an intervening sequence of 9 bp. The composite structure of the longer alleles closely resembles that of the 12 human D12S67 alleles (229-273 bp). The enormous species variation in the fragment size range, with the smallest allele found in Macaca mulatta (108 bp) and the largest (364 bp) in Gorilla gorilla gorilla strongly indicates that D12s67 has been subjected to recurrent mutations over the course of primate evolution including a large deletion and/or insertion event.

Alleles↗
PubMed2003

Human growth hormone 1 (GH1) gene expression: complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region.

The proximal promoter region of the human pituitary expressed growth hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex.

Adult↗
PubMed1992

Replication errors may contribute to the generation of large deletions and duplications in the dystrophin gene.

Frequent recurrent mutations of the human dystrophin gene lead to Duchenne and Becker muscular dystrophies. Although the approximately 2.5 Mb size of the gene may form a large target for mutations it is not clear to date which mechanisms promote the observed high frequency of spontaneous mutants (1 in 10,000 X-chromosomes) of which a high percentage (> 70%) are gross structural aberrations (deletions/duplications). In order to gain insight into possible molecular mechanisms we have cloned and sequenced the deletion junction fragments from two unrelated Duchenne patients. Our data, together with a short review on other cases from the literature, present evidence that errors of DNA replication may contribute to the generation of submicroscopic chromosome rearrangements.

Amino Acid Sequence↗