scholarly journals Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Priti Singh ◽  
Robert Fragoza ◽  
Cecilia S. Blengini ◽  
Tina N. Tran ◽  
Gianno Pannafino ◽  
...  
Keyword(s):  
Pregnancy Loss ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Homologous Chromosomes ◽  
Hypomorphic Alleles ◽  
Two Hybrid ◽  
Embryo Resorption ◽  
Computational Predictions ◽  
Segregation Of Chromosomes

AbstractEmbryonic aneuploidy from mis-segregation of chromosomes during meiosis causes pregnancy loss. Proper disjunction of homologous chromosomes requires the mismatch repair (MMR) genes MLH1 and MLH3, essential in mice for fertility. Variants in these genes can increase colorectal cancer risk, yet the reproductive impacts are unclear. To determine if MLH1/3 single nucleotide polymorphisms (SNPs) in human populations could cause reproductive abnormalities, we use computational predictions, yeast two-hybrid assays, and MMR and recombination assays in yeast, selecting nine MLH1 and MLH3 variants to model in mice via genome editing. We identify seven alleles causing reproductive defects in mice including female subfertility and male infertility. Remarkably, in females these alleles cause age-dependent decreases in litter size and increased embryo resorption, likely a consequence of fewer chiasmata that increase univalents at meiotic metaphase I. Our data suggest that hypomorphic alleles of meiotic recombination genes can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.

scholarly journals MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging

2021 ◽  
Author(s):  
Priti Singh ◽  
Robert Fragoza ◽  
Cecilia S. Blengini ◽  
Tina N. Tran ◽  
Gianno Pannafino ◽  
...  
Keyword(s):  
Pregnancy Loss ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Homologous Chromosomes ◽  
Precise Control ◽  
Sperm Counts ◽  
Hypomorphic Alleles ◽  
Two Hybrid ◽  
Computational Predictions

AbstractMost spontaneous pregnancy losses are a result of embryonic aneuploidy stemming from mis-segregation of chromosomes during meiosis. Proper disjunction of homologous chromosomes is dependent upon precise control of crossing-over, a process requiring the mismatch repair (MMR) genes MLH1 and MLH3. Both are required for fertility and completion of meiosis in mice. People inheriting variants in these genes are often at high risk for colorectal cancer and Lynch syndrome, yet the potential impacts of variants upon reproduction are unclear. To determine if MLH1/3 variants (namely single nucleotide polymorphisms, or SNPs) in human populations can cause reproductive abnormalities, we used a combination of computational predictions, yeast two-hybrid assays, and assays of MMR and recombination in yeast to select nine MLH1 and MLH3 variants for modeling in mice via genome editing. We identified 7 alleles that caused reproductive defects in mice including subfertility in females, male infertility, reduced sperm counts, and increased spermatocyte apoptosis. Remarkably, these alleles in females caused age-dependent decreases in litter size, and increased resorption of embryos during pregnancy. These outcomes were likely a consequence of reduced meiotic chiasmata, in turn causing an increase in misaligned chromosomes and univalents in meiotic metaphase I (MI). Our data indicate that segregating hypomorphic alleles of meiotic recombination genes in populations can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.

scholarly journals Genetics of Lactose Intolerance: An Updated Review and Online Interactive World Maps of Phenotype and Genotype Frequencies

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2689
Author(s):  
Augusto Anguita-Ruiz ◽  
Concepción M. Aguilera ◽  
Ángel Gil
Keyword(s):  
Genetic Basis ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genotype Frequencies ◽  
Genetic Mechanisms ◽  
Visualization Tools ◽  
Available Information ◽  
Static World ◽  
Interactive Resources

In humans the ability to digest milk lactose is conferred by a β-galactosidase enzyme called lactase-phlorizin hydrolase (LPH). While in some humans (approximately two-thirds of humankind) the levels of this enzyme decline drastically after the weaning phase (a trait known as lactase non-persistence (LNP)), some other individuals are capable of maintaining high levels of LPH lifelong (lactase persistence (LP)), thus being able to digest milk during adulthood. Both lactase phenotypes in humans present a complex genetic basis and have been widely investigated during the last decades. The distribution of lactase phenotypes and their associated single nucleotide polymorphisms (SNPs) across human populations has also been extensively studied, though not recently reviewed. All available information has always been presented in the form of static world maps or large dimension tables, so that it would benefit from the newly available visualization tools, such as interactive world maps. Taking all this into consideration, the aims of the present review were: (1) to gather and summarize all available information on LNP and LP genetic mechanisms and evolutionary adaptation theories, and (2) to create online interactive world maps, including all LP phenotype and genotype frequency data reported to date. As a result, we have created two online interactive resources, which constitute an upgrade over previously published static world maps, and allow users a personalized data exploration, while at the same time accessing complete reports by population or ethnicity.

Genetic Modulation of Adrenergic Activity in the Heart and Vasculature: Implications for Perioperative Medicine

2005 ◽  
Vol 102 (2) ◽  
pp. 429-446 ◽  
Author(s):  
Michael Zaugg ◽  
Marcus C. Schaub ◽  
David C. Warltier
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Association Studies ◽  
Perioperative Medicine ◽  
Adrenergic System ◽  
Human Populations ◽  
Receptor Subtypes ◽  
Primary Control ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Small Series

The adrenergic system provides the primary control for cardiac, vascular, pulmonal, and metabolic functions. Seven of the nine adrenergic receptor subtypes display mutations that affect their function. Results from transgenic mouse models and from association studies in human populations allow to link protein dysfunctions to cardiovascular diseases or to risk for disease development. The disease contribution by single nucleotide polymorphisms may be small. Series of single nucleotide polymorphisms along a chromosome are combined in haplotypes and inherited together. Individual single nucleotide polymorphisms in a haplotype can influence each other and lead to new, unpredictable phenotypes. Haplotypes vary widely among different ethnic groups. In this review, we discuss the genetic organization of single nucleotide polymorphisms and haplotypes in the adrenergic system and their implications for the heart and vasculature with special reference to perioperative medicine. With the advent of powerful genomic technologies, genotyping may become standard in patient evaluation and will help to individualize therapeutic approaches.

scholarly journals Optimal Haplotype Assembly from High-Throughput Mate-Pair Reads

2015 ◽  
Author(s):  
Govinda M Kamath ◽  
Eren Şaşoğlu ◽  
David Tse
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
High Throughput ◽  
Simple Formula ◽  
Homologous Chromosome ◽  
Convolutional Codes ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Homologous Chromosomes ◽  
Haplotype Assembly ◽  
Mate Pair

Humans have $23$ pairs of homologous chromosomes. The homologous pairs are almost identical pairs of chromosomes. For the most part, differences in homologous chromosome occur at certain documented positions called single nucleotide polymorphisms (SNPs).A haplotype of an individual is the pair of sequences of SNPs on the two homologous chromosomes. In this paper, we study the problem of inferring haplotypes of individuals from mate-pair reads of their genome. We give a simple formula for the coverage needed for haplotype assembly, under a generative model. The analysis here leverages connections of this problem with decoding convolutional codes.

scholarly journals Mining SNPs From EST Databases

1999 ◽  
Vol 9 (2) ◽  
pp. 167-174 ◽  
Author(s):  
Leslie Picoult-Newberg ◽  
Trey E. Ideker ◽  
Mark G. Pohl ◽  
Scott L. Taylor ◽  
Miriam A. Donaldson ◽  
...  
Keyword(s):  
Expressed Sequence Tag ◽  
De Novo ◽  
Cdna Libraries ◽  
Human Populations ◽  
Data Sets ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Using Data

There is considerable interest in the discovery and characterization of single nucleotide polymorphisms (SNPs) to enable the analysis of the potential relationships between human genotype and phenotype. Here we present a strategy that permits the rapid discovery of SNPs from publicly available expressed sequence tag (EST) databases. From a set of ESTs derived from 19 different cDNA libraries, we assembled 300,000 distinct sequences and identified 850 mismatches from contiguous EST data sets (candidate SNP sites), without de novo sequencing. Through a polymerase-mediated, single-base, primer extension technique, Genetic Bit Analysis (GBA), we confirmed the presence of a subset of these candidate SNP sites and have estimated the allele frequencies in three human populations with different ethnic origins. Altogether, our approach provides a basis for rapid and efficient regional and genome-wide SNP discovery using data assembled from sequences from different libraries of cDNAs.[The SNPs identified in this study can be found in the National Center of Biotechnology (NCBI) SNP database under submitter handles ORCHID (SNPS-981210-A) and debnick (SNPS-981209-A and SNPS-981209-B).]

scholarly journals Nutrigenetics: links between genetic background and response to Mediterranean-type diets

2009 ◽  
Vol 12 (9A) ◽  
pp. 1601-1606 ◽  
Author(s):  
Denis Lairon ◽  
Catherine Defoort ◽  
Jean-Charles Martin ◽  
Marie-Jo Amiot-Carlin ◽  
Marguerite Gastaldi ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Genetic Background ◽  
Dietary Intervention ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Dietary Recommendations ◽  
Single Nucleotide ◽  
Fatty Acid Binding ◽  
Genetic Traits ◽  
Transfer Protein

AbstractObjectiveIt has been substantiated that the onset of most major diseases (CVD, diabetes, obesity, cancers, etc.) is modulated by the interaction between genetic traits (susceptibility) and environmental factors, especially diet. We aim to report more specific observations relating the effects of Mediterranean-type diets on cardiovascular risk factors and the genetic background of subjects.Results and conclusionsIn the first part, general concepts about nutrigenetics are briefly presented. Human genome has, overall, only marginally changed since its origin but it is thought that minor changes (polymorphisms) of common genes that occurred during evolution are now widespread in human populations, and can alter metabolic pathways and response to diets.In the second part, we report the data obtained during the Medi-RIVAGE intervention study performed in the South-East of France. Data obtained in 169 subjects at moderate cardiovascular risk after a 3-month dietary intervention indicate that some of the twenty-three single nucleotide polymorphisms (SNP) studied exhibit interactions with diets regarding changes of particular parameters after 3-month regimens. Detailed examples are presented, such as interactions between SNP in genes coding for microsomial transfer protein (MTTP) or intestinal fatty acid binding protein (FABP2) and triglyceride, LDL-cholesterol or Framigham score lowering in responses to Mediterranean-type diets.The data provided add further evidence of the interaction between particular SNP and metabolic responses to diets. Finally, improvement in dietary recommendations by taking into account known genetic variability has been discussed.

scholarly journals Effects of Six Functional SNPs on the Urinary 8-Isoprostane Level in a General Japanese Population; Shimane COHRE Study

2011 ◽  
Vol 30 (6) ◽  
pp. 291-298 ◽  
Author(s):  
Yoji Suyama ◽  
Chikashi Matsuda ◽  
Minoru Isomura ◽  
Tsuyoshi Hamano ◽  
Kenji Karino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Genetic Factors ◽  
Linear Regression Analysis ◽  
Mthfr C677t ◽  
Cross Sectional Study ◽  
Human Populations ◽  
Health Examination ◽  
Nucleotide Polymorphisms ◽  
Cross Sectional ◽  
Single Nucleotide

Oxidative stress is an important risk factor for cardiovascular diseases. Although a variety of genetic factors are assumed to contribute to the regulation of oxidative stress, evidence in human populations is insufficient. In this study, we therefore evaluated the effects of six functional single-nucleotide polymorphisms (SNPs) on the oxidative stress under a cross-sectional study design. Participants of the health examination in two neighboring counties were recruited in a mountainous region of Shimane prefeture, Japan (n= 1092). As a marker for the oxidative stress, the urinary 8-isoprostane (IsoP) was measured by ELISA. The six SNPs were genotyped using the Taqman method. None of the SNPs showed a significant effect on the IsoP level. However, the Generalized Multiple Dimensionality Reduction (GMDR) method identified that the combination of the two SNPs, MTHFR C677T and eNOS T-786C, showed a significant effect on the IsoP level in this population. The linear regression analysis confirmed that the high risk genotype identified in the GMDR was an independent factor influencing the IsoP even after adjustment of confounding factors. This result suggested that GMDR analysis might be useful to identify concealed effects of combined SNPs.

scholarly journals Relationship between the genetic structure of human populations and geographical and climatic parameters

2018 ◽  
pp. 37-40
Author(s):  
А.А. Попович ◽  
К.В. Вагайцева ◽  
А.В. Бочарова ◽  
В.А. Степанов
Keyword(s):  
Genetic Diversity ◽  
Modern Human ◽  
Cold Climate ◽  
Human Populations ◽  
Genetic Constitution ◽  
Nucleotide Polymorphisms ◽  
Climatic Parameters ◽  
Single Nucleotide ◽  
Variability Analysis ◽  
The Earth

Популяции человека проживают в различных условиях среды обитания, которые требуют адаптации, особенно к экстремальным средовым факторам. Действие адаптивной эволюции отражается и на генетической структуре популяций человека. В настоящем исследовании был проведен анализ вариабельности 25 однонуклеотидных полиморфизмов (SNP), связанных с адаптацией к холодному климату, в мировых популяциях. Показано влияние климатических и географических факторов на генетическое разнообразие популяций человека. Выявлен рост генетического разнообразия по изученным маркерам от Африки по мере расселения современного человека по земному шару. Вероятно, высокая частота аллелей, ассоциированных с адаптацией к климату, в некоторых популяциях человека может быть объяснена в рамках гипотезы канализации/деканализации геном-феномных отношений в ходе расселения современного человека. Human populations live in different environmental conditions that require adaptation, especially to extreme environmental factors. The action of adaptive evolution is also reflected on human populations’ genetic constitution. The study highlights the variability analysis of 25 SNPs single nucleotide polymorphisms (SNP) related to adaptation to a cold climate, as well as influence of climatic and geographical factors on the genetic diversity of human populations. The growth of the genetic diversity among the studied markers from Africa according to a modern human’s displacement around the earth identified. Probably, the variability of alleles associated with adaptation to climate in some populations could be explained in the framework of the hypothesis of canalization/decanalization of genome-phenome relationships under natural selection during modern human dispersion.

Sign in / Sign up

Export Citation Format

Share Document