scholarly journals Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3

2013 ◽  
Vol 45 (15) ◽  
pp. 667-683 ◽  
Author(s):  
Jessica H. Geahlen ◽  
Carlo Lapid ◽  
Kaisa Thorell ◽  
Igor Nikolskiy ◽  
Won Jae Huh ◽  
...  
Keyword(s):  
Selective Sweep ◽  
Stop Codon ◽  
Genetic Locus ◽  
Donor Site ◽  
Premature Stop Codon ◽  
Population Based ◽  
Splice Donor Site ◽  
Human Populations ◽  
Selective Sweeps ◽  
Gastric Mucous

In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.

scholarly journals A rare large duplication of MLH1 identified in Lynch syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Kumar ◽  
Nagarajan Paramasivam ◽  
Obul Reddy Bandapalli ◽  
Matthias Schlesner ◽  
Tianhui Chen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lynch Syndrome ◽  
Splice Site ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Splice Donor Site ◽  
Laboratory Diagnostics ◽  
Mmr Genes ◽  
Base Pair Deletion ◽  
Splice Site Variant

Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

scholarly journals Succinate Dehydrogenase (SDH) D Subunit (SDHD) Inactivation in a Growth-Hormone-Producing Pituitary Tumor: A New Association for SDH?

2012 ◽  
Vol 97 (3) ◽  
pp. E357-E366 ◽  
Author(s):  
Paraskevi Xekouki ◽  
Karel Pacak ◽  
Madson Almeida ◽  
Christopher A. Wassif ◽  
Pierre Rustin ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Loss Of Heterozygosity ◽  
Pituitary Tumor ◽  
Stop Codon ◽  
Genetic Locus ◽  
Premature Stop Codon ◽  
Pituitary Tumors ◽  
Tumor Formation ◽  
Protein Loss ◽  
Down Regulation

Background: Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD). Aim: Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma. Patients and Methods: A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors. Conclusion: We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.

scholarly journals The molecular genetic basis of Glanzmann's thrombasthenia in a gypsy population in France: identification of a new mutation on the alpha IIb gene

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 977-982 ◽  
Author(s):  
N Schlegel ◽  
O Gayet ◽  
MC Morel-Kopp ◽  
B Wyler ◽  
MF Hurtaud-Roux ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Donor Site ◽  
Molecular Genetic ◽  
Premature Stop Codon ◽  
Splice Donor Site ◽  
Pcr Analysis ◽  
New Mutation ◽  
Glanzmann’S Thrombasthenia ◽  
Molecular Genetic Basis ◽  
Glanzmann's Thrombasthenia

Glanzmann's thrombasthenia is a rare inherited bleeding disorder caused by a qualitative or quantitative defect of platelet alpha IIb beta 3. We describe here a new mutation that is the molecular genetic basis of Glanzmann's thrombasthenia in two gypsy families. Our investigation was focused on the alpha IIb gene as a result of biochemical and immunologic analysis of patients' platelets showing undetectable alpha IIb but residual beta 3 levels. The entire alpha IIb cDNA was polymerase chain reaction (PCR) amplified using patients platelet RNA. Sequence analysis showed an 8-bp deletion located at the 3′ end of exon 15. This deletion causes a reading-frame shift leading to a premature stop codon and the synthesis of a severely truncated form of alpha IIb. Genomic DNA study showed a G-->A substitution, the Gypsy mutation, at the splice donor site of intron 15. This mutation results in an abnormal splicing occurring at an alternative donor site located 8 bp upstream from the mutation. Based on those results, an allele-specific PCR analysis was developed to allow a rapid identification of the mutation in patients and potential carriers of the gypsy community. This PCR analysis can also be used for genetic counseling and antenatal diagnosis.

scholarly journals R577X polymorphism of alpha-actinin-3 in human populations of North-Eastern Asia

2017 ◽  
Vol 15 (1) ◽  
pp. 50
Author(s):  
Boris A Malyarchuk ◽  
Miroslava V Derenko ◽  
Galina A Denisova
Keyword(s):  
Cold Adaptation ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Muscle Metabolism ◽  
Enzymatic Digestion ◽  
Muscle Performance ◽  
Human Populations ◽  
Eastern Asia ◽  
North East ◽  
North Eastern

Background. In polymorphism rs1815739, a C → T transition converts arginine to a premature stop-codon at residue 577 of the alpha-actinin-3 (ACTN3) protein (R577X polymorphism). This polymorphism may affect muscle performance, and the derived 577X allele has been found to be under-represented in sprint/power athletes. In addition, loss of alpha-actinin-3 results in a shift in muscle metabolism toward the more efficient aerobic pathway, thus pointing that this polymorphism may have been involved in enhancing the capability for hunting and for cold adaptation. Here, we study rs1815739 polymorphism in native populations (Chukchi, Koryaks and Evens) and newcomers (Russians) of North-Eastern Asia. Materials and methods. Genomic DNA was isolated from peripheral blood. ACTN3 genotypes for rs1815739 locus were established by enzymatic digestion of amplicons with DdeI. Heterozygotes TT were confirmed by DNA sequencing. In addition, data on exome variation in Siberian populations were analyzed. Results. Lowered frequencies (less than 40%) of “mutant” allele rs1815739-T were found in studied populations of North-Eastern Asia. Analysis of exome data has shown that haplotype comprising the rs1815739-T allele reaches the highest frequencies in populations of Southern and Central Siberia, while it is rather rare in the north-east of Siberia. Conclusion. The results obtained contradict the hypothesis that the rs1815739 polymorphism may have been involved in cold adaptation of North-East Siberians.

scholarly journals Band 3 Campinas: A Novel Splicing Mutation in the Band 3 Gene (AE1 ) Associated With Hereditary Spherocytosis, Hyperactivity of Na+/Li+ Countertransport and an Abnormal Renal Bicarbonate Handling

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2810-2818 ◽  
Author(s):  
Paulo R.M. Lima ◽  
José A.R. Gontijo ◽  
José B. Lopes de Faria ◽  
Fernando F. Costa ◽  
Sara T.O. Saad
Keyword(s):  
Hereditary Spherocytosis ◽  
Stop Codon ◽  
Collecting Duct ◽  
Direct Sequencing ◽  
Donor Site ◽  
Premature Stop Codon ◽  
Band 3 ◽  
Base Substitution ◽  
Molecular Defect ◽  
Urinary Acidification

Abstract We have studied the molecular defect underlying band 3 deficiency in one family with hereditary spherocytosis using nonradioactive single strand conformation polimorphism of polymerase chain reaction (PCR) amplified genomic DNA of the AE1 gene. By direct sequencing, a single base substitution in the splicing donor site of intron 8 (position + 1G → T) was identified. The study of the cDNA showed a skipping of exon 8. This exon skipping event is responsible for a frameshift leading to a premature stop codon 13 amino acids downstream. The distal urinary acidification test by furosemide was performed to verify the consequences of the band 3 deficiency in α intercalated cortical collecting duct cells (αICCDC). We found an increased basal urinary bicarbonate excretion, associated with an increased basal urinary pH and an efficient distal urinary acidification. We also tested the consequences of band 3 deficiency on the Na+/H+ exchanger, by the measurement of Na+/Li+ countertransport activity in red blood cells. The Na+/Li+ countertransport activity was increased threefold to sixfold in the patients compared with the controls. It is possible that band 3 deficiency in the kidney leads to a decrease in the reabsorption of HCO−3 in αICCDC and anion loss, which might be associated with an increased sodium-lithium countertransport activity.

scholarly journals A Likelihood Approach for Uncovering Selective Sweep Signatures from Haplotype Data

2020 ◽  
Vol 37 (10) ◽  
pp. 3023-3046
Author(s):  
Alexandre M Harris ◽  
Michael DeGiorgio
Keyword(s):  
Selective Sweep ◽  
Natural Populations ◽  
Haplotype Frequency ◽  
Human Populations ◽  
Ratio Test ◽  
Whole Genome ◽  
Selective Sweeps ◽  
Test Statistic ◽  
Haplotypic Diversity ◽  
Haplotype Data

Abstract Selective sweeps are frequent and varied signatures in the genomes of natural populations, and detecting them is consequently important in understanding mechanisms of adaptation by natural selection. Following a selective sweep, haplotypic diversity surrounding the site under selection decreases, and this deviation from the background pattern of variation can be applied to identify sweeps. Multiple methods exist to locate selective sweeps in the genome from haplotype data, but none leverages the power of a model-based approach to make their inference. Here, we propose a likelihood ratio test statistic T to probe whole-genome polymorphism data sets for selective sweep signatures. Our framework uses a simple but powerful model of haplotype frequency spectrum distortion to find sweeps and additionally make an inference on the number of presently sweeping haplotypes in a population. We found that the T statistic is suitable for detecting both hard and soft sweeps across a variety of demographic models, selection strengths, and ages of the beneficial allele. Accordingly, we applied the T statistic to variant calls from European and sub-Saharan African human populations, yielding primarily literature-supported candidates, including LCT, RSPH3, and ZNF211 in CEU, SYT1, RGS18, and NNT in YRI, and HLA genes in both populations. We also searched for sweep signatures in Drosophila melanogaster, finding expected candidates at Ace, Uhg1, and Pimet. Finally, we provide open-source software to compute the T statistic and the inferred number of presently sweeping haplotypes from whole-genome data.

A Microsatellite-Based Multilocus Screen for the Identification of Local Selective Sweeps

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 753-763 ◽  
Author(s):  
Christian Schlötterer
Keyword(s):  
Microsatellite Loci ◽  
Selective Sweep ◽  
Demographic History ◽  
Human Populations ◽  
Selective Sweeps ◽  
Test Statistic ◽  
Data Set ◽  
History Of ◽  
Microsatellite Mutation ◽  
Genomic Regions

AbstractWith the availability of completely sequenced genomes, multilocus scans of natural variability have become a feasible approach for the identification of genomic regions subjected to natural and artificial selection. Here, I introduce a new multilocus test statistic, ln RV, which is based on the ratio of observed variances in repeat number at a set of microsatellite loci in two groups of populations. The distribution of ln RV values captures demographic history of the populations as well as variation in microsatellite mutation among loci. Given that microsatellite loci associated with a recent selective sweep differ from the remainder of the genome, they are expected to fall outside of the distribution of neutral ln RV values. The ln RV test statistic is applied to a data set of 94 loci typed in eight non-African and two African human populations.

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