Relevant bibliographies by topics / Human genetic variants

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  2. Dissertations / Theses
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Academic literature on the topic 'Human genetic variants'

Author: Grafiati
Published: 12 April 2025

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Journal articles on the topic "Human genetic variants"

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Gifford, Casey A., Sanjeev S. Ranade, Ryan Samarakoon, Hazel T. Salunga, T. Yvanka de Soysa, Yu Huang, Ping Zhou, et al. "Oligogenic inheritance of a human heart disease involving a genetic modifier." Science 364, no. 6443 (May 30, 2019): 865–70. http://dx.doi.org/10.1126/science.aat5056.

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Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell–derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant’s contribution as a genetic modifier.
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Fan, Wenjun, Eetu Eklund, Rachel M. Sherman, Hester Liu, Stephanie Pitts, Brittany Ford, N. V. Rajeshkumar, and Marikki Laiho. "Widespread genetic heterogeneity of human ribosomal RNA genes." RNA 28, no. 4 (February 2, 2022): 478–92. http://dx.doi.org/10.1261/rna.078925.121.

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Polymorphism drives survival under stress and provides adaptability. Genetic polymorphism of ribosomal RNA (rRNA) genes derives from internal repeat variation of this multicopy gene, and from interindividual variation. A considerable amount of rRNA sequence heterogeneity has been proposed but has been challenging to estimate given the scarcity of accurate reference sequences. We identified four rDNA copies on chromosome 21 (GRCh38) with 99% similarity to recently introduced reference sequence KY962518.1. We customized a GATK bioinformatics pipeline using the four rDNA loci, spanning a total 145 kb, for variant calling and used high-coverage whole-genome sequencing (WGS) data from the 1000 Genomes Project to analyze variants in 2504 individuals from 26 populations. We identified a total of 3791 variant positions. The variants positioned nonrandomly on the rRNA gene. Invariant regions included the promoter, early 5′ ETS, most of 18S, 5.8S, ITS1, and large areas of the intragenic spacer. A total of 470 variant positions were observed on 28S rRNA. The majority of the 28S rRNA variants were located on highly flexible human-expanded rRNA helical folds ES7L and ES27L, suggesting that these represent positions of diversity and are potentially under continuous evolution. Several variants were validated based on RNA-seq analyses. Population analyses showed remarkable ancestry-linked genetic variance and the presence of both high penetrance and frequent variants in the 5′ ETS, ITS2, and 28S regions segregating according to the continental populations. These findings provide a genetic view of rRNA gene array heterogeneity and raise the need to functionally assess how the 28S rRNA variants affect ribosome functions.
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Hutchinson, Anna, Jennifer Asimit, and Chris Wallace. "Fine-mapping genetic associations." Human Molecular Genetics 29, R1 (August 3, 2020): R81—R88. http://dx.doi.org/10.1093/hmg/ddaa148.

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Abstract Whilst thousands of genetic variants have been associated with human traits, identifying the subset of those variants that are causal requires a further ‘fine-mapping’ step. We review the basic fine-mapping approach, which is computationally fast and requires only summary data, but depends on an assumption of a single causal variant per associated region which is recognized as biologically unrealistic. We discuss different ways that the approach has been built upon to accommodate multiple causal variants in a region and to incorporate additional layers of functional annotation data. We further review methods for simultaneous fine-mapping of multiple datasets, either exploiting different linkage disequilibrium (LD) structures across ancestries or borrowing information between distinct but related traits. Finally, we look to the future and the opportunities that will be offered by increasingly accurate maps of causal variants for a multitude of human traits.
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Khanna, Tarun, Gordon Hanna, Michael J. E. Sternberg, and Alessia David. "Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants." Human Genetics 140, no. 5 (January 27, 2021): 805–12. http://dx.doi.org/10.1007/s00439-020-02246-z.

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AbstractThe interpretation of human genetic variation is one of the greatest challenges of modern genetics. New approaches are urgently needed to prioritize variants, especially those that are rare or lack a definitive clinical interpretation. We examined 10,136,597 human missense genetic variants from GnomAD, ClinVar and UniProt. We were able to perform large-scale atom-based mapping and phenotype interpretation of 3,960,015 of these variants onto 18,874 experimental and 84,818 in house predicted three-dimensional coordinates of the human proteome. We demonstrate that 14% of amino acid substitutions from the GnomAD database that could be structurally analysed are predicted to affect protein structure (n = 568,548, of which 566,439 rare or extremely rare) and may, therefore, have a yet unknown disease-causing effect. The same is true for 19.0% (n = 6266) of variants of unknown clinical significance or conflicting interpretation reported in the ClinVar database. The results of the structural analysis are available in the dedicated web catalogue Missense3D-DB (http://missense3d.bc.ic.ac.uk/). For each of the 4 M variants, the results of the structural analysis are presented in a friendly concise format that can be included in clinical genetic reports. A detailed report of the structural analysis is also available for the non-experts in structural biology. Population frequency and predictions from SIFT and PolyPhen are included for a more comprehensive variant interpretation. This is the first large-scale atom-based structural interpretation of human genetic variation and offers geneticists and the biomedical community a new approach to genetic variant interpretation.
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Keogh, Michael J., Wei Wei, Juvid Aryaman, Ian Wilson, Kevin Talbot, Martin R. Turner, Chris-Anne McKenzie, et al. "Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 8 (January 13, 2018): 813–16. http://dx.doi.org/10.1136/jnnp-2017-317234.

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BackgroundSeveral studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series.MethodsWe analysed 980 neuropathologically characterised human brains with Alzheimer’s disease (AD), Parkinson’s disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity. Individuals with two or more variants within a relevant disease gene panel were defined as ‘oligogenic’.ResultsThe majority of oligogenic variant combinations consisted of a highly penetrant allele or known risk factor in combination with another rare but likely benign allele. The presence of oligogenic variants did not influence the age of onset or disease severity. After controlling for the single known major risk allele, the frequency of oligogenic variants was no different between cases and controls.ConclusionsA priori, individuals with AD, PD-DLB and FTD-ALS are more likely to harbour a known genetic risk factor, and it is the burden of these variants in combination with rare benign alleles that is likely to be responsible for some oligogenic associations. Controlling for this bias is essential in studies investigating a potential role for oligogenic variation in neurodegenerative diseases.
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Kamat, Mihir A., James A. Blackshaw, Robin Young, Praveen Surendran, Stephen Burgess, John Danesh, Adam S. Butterworth, and James R. Staley. "PhenoScanner V2: an expanded tool for searching human genotype–phenotype associations." Bioinformatics 35, no. 22 (June 24, 2019): 4851–53. http://dx.doi.org/10.1093/bioinformatics/btz469.

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Abstract Summary PhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates ‘phenome scans’, where genetic variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner (‘PhenoScanner V2’), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants. Availability and implementation PhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk.
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Young, Barry P., Kathryn L. Post, Jesse T. Chao, Fabian Meili, Kurt Haas, and Christopher Loewen. "Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast." Disease Models & Mechanisms 13, no. 7 (May 29, 2020): dmm044560. http://dx.doi.org/10.1242/dmm.044560.

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ABSTRACTAdvances in sequencing technology have led to an explosion in the number of known genetic variants of human genes. A major challenge is to now determine which of these variants contribute to diseases as a result of their effect on gene function. Here, we describe a generic approach using the yeast Saccharomyces cerevisiae to quickly develop gene-specific in vivo assays that can be used to quantify the level of function of a genetic variant. Using synthetic dosage lethality screening, ‘sentinel’ yeast strains are identified that are sensitive to overexpression of a human disease gene. Variants of the gene can then be functionalized in a high-throughput fashion through simple growth assays using solid or liquid media. Sentinel interaction mapping (SIM) has the potential to create functional assays for the large majority of human disease genes that do not have a yeast orthologue. Using the tumour suppressor gene PTEN as an example, we show that SIM assays can provide a fast and economical means to screen a large number of genetic variants.
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Köksal, Zehra, Claus Børsting, Leonor Gusmão, and Vania Pereira. "SNPtotree—Resolving the Phylogeny of SNPs on Non-Recombining DNA." Genes 14, no. 10 (September 22, 2023): 1837. http://dx.doi.org/10.3390/genes14101837.

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Genetic variants on non-recombining DNA and the hierarchical order in which they accumulate are commonly of interest. This variant hierarchy can be established and combined with information on the population and geographic origin of the individuals carrying the variants to find population structures and infer migration patterns. Further, individuals can be assigned to the characterized populations, which is relevant in forensic genetics, genetic genealogy, and epidemiologic studies. However, there is currently no straightforward method to obtain such a variant hierarchy. Here, we introduce the software SNPtotree v1.0, which uniquely determines the hierarchical order of variants on non-recombining DNA without error-prone manual sorting. The algorithm uses pairwise variant comparisons to infer their relationships and integrates the combined information into a phylogenetic tree. Variants that have contradictory pairwise relationships or ambiguous positions in the tree are removed by the software. When benchmarked using two human Y-chromosomal massively parallel sequencing datasets, SNPtotree outperforms traditional methods in the accuracy of phylogenetic trees for sequencing data with high amounts of missing information. The phylogenetic trees of variants created using SNPtotree can be used to establish and maintain publicly available phylogeny databases to further explore genetic epidemiology and genealogy, as well as population and forensic genetics.
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Franti, Michael, Antoine Gessain, Pierre Darlu, Agnès Gautheret-Dejean, Haruhiko Kosuge, Philippe Mauclère, Jean-Thierry Aubin, Vladimir Gurtsevitch, Koichi Yamanishi, and Henri Agut. "Genetic polymorphism of human herpesvirus-7 among human populations." Journal of General Virology 82, no. 12 (December 1, 2001): 3045–50. http://dx.doi.org/10.1099/0022-1317-82-12-3045.

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The analysis of three human herpesvirus-7 (HHV-7) genes encoding phosphoprotein p100, glycoprotein B and major capsid protein respectively had previously shown the existence of distinct gene alleles, leading to the concept of HHV-7 variants. We have analysed the distribution of HHV-7 variants among 297 distinct subjects who belonged to different human populations from Africa, Asia, Europe and America. Two variants, designated Co1 and Co2, were found in 52% and 20% of studied subjects. Ten other variants, designated Co3–Co12, were less frequent and classified into two groups related to Co1 and Co2 respectively. While the former group was ubiquitous and the most frequent in Africa and Asia, the latter one was predominantly found in European and Mongol populations. Despite the high stability of the HHV-7 genome, a few nucleotide substitutions at precise positions define distinct variants which, to some extent, behave as markers of human populations.
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Spurdle, Amanda B., Stephanie Greville-Heygate, Antonis C. Antoniou, Melissa Brown, Leslie Burke, Miguel de la Hoya, Susan Domchek, et al. "Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report." Journal of Medical Genetics 56, no. 6 (April 8, 2019): 347–57. http://dx.doi.org/10.1136/jmedgenet-2018-105872.

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The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high-throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumour DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate among scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.
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Dissertations / Theses on the topic "Human genetic variants"

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Okyere-Boakye, Ivan W. "Studies on genetic variants of human plasma transferrin." Thesis, Queen Mary, University of London, 1997. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1639.

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The work presented in this thesis is concerned with the characterisation of human plasma transferrins showing abnormal electrophoretic mobilities on polyacrylamide gels. The work is divided into three studies: (i) a study of transferrin variants detected by nondenaturing polyacrylamide gel electrophoresis; (ii) a study of the plasma concentrations of individuals showing transferrin phenotypes associated with the three most common Tf C alleles, Tf Cl, Tf C2 and Tf C3; and (iii) a study of a reported nondegenerate nucleotide difference in the sequence of the cloned human transferrin gene. In the first study, six transferrin variants (3 Tf Br,,.,,, s and 3 Tf D. 5) showing abnormal electrophoretic mobilities on nondenaturing polyacrylamide gels, and the two Tf C variants, Tf Cl and Tf C2 which occur at polymorphic levels (> 1%) in human populations, were isolated and purified from human plasma. Transferrins were purified by a combination of DEAE Sephacel anion-exchange chromatography, SP. Sephadex cation-exchange chromatography and G-200 gel-filtration chromatography. A series of comparative studies were then carried out on the isolated transferrins to determine whether the six transferrin variants detected in this thesis and the Tf C2 variant, showed similar characteristics to the wild-type Tf Cl. Transferrins were studied for sialic acid content of the two glycan chains, and for molecular weights and isoelectric points of the iron-free (apo) and iron-saturated (holo) transferrin forms. Metal-binding properties were examined by studying the binding of Fe", Cu", Al" and Ga"'. Iron-binding was studied at physiological and endosomal pH (7.5 and 5.5 respectively) using FENTA as the iron donor. Binding of Cue*, Al"' and Ga'* were examined at physiological pH using CUNTA, ALNTA and GANTA respectively. The ability of transferrins to retain bound iron was examined by studying pH-induced iron release over a pH range of 6.0-4.0. Conformational stabilities were determined by studying the iron-binding abilities of apotransferrins following exposure to urea or thermal denaturation, and by studying iron loss from holo transferrins following exposure to urea or thermal denaturation. Other than expected differences in isoelectric points, and slightly faster rates of iron loss from variant holo transferrins titrated at physiological pH, all variant transferrins were found to show similar characteristics to Tf Cl, with identical molecular weights and sialic acid content, similar metal-binding properties, and similar stabilities to urea or thermal denaturation. The results indicate that the structure and function of the variant transferrins are not adversely affected by their differences in primary structure. The second study examined the relationship between plasma transferrin concentration and transferrin phenotypes representing five of the six most common Tf C phenotypes (i. e. Tf Cl, Tf C2, Tf C2-1, Tf C3-1 and Tf C3-2), to determine whether plasma concentrations were dependent on transferrin phenotype as suggested in literature. Transferrin phenotypes of 931 unrelated individuals were determined by electrophoresis of plasma on polyacrylamide isoelectric focusing gels. Plasma transferrin concentrations were determined by single radial immunodiffusion using rabbit anti-human transferrin IgG. A significant difference was found between the plasma concentrations of the five transferrin phenotypes (p < 0.01) indicating that transferrin concentration was dependent on phenotype. The results suggest that the two Tf C alleles, Tf C2 and Tf C3 are associated with low plasma concentrations. The third study was initiated to investigate a report in literature that a nondegenerate nucleotide difference of adenine for guanine at base 1086 in exon 8 of the human transferrin gene, may indicate the presence of a hitherto unrecognised transferrin variant with Asn rather than a wild-type Asp at position 310 of the amino acid sequence. The nucleotide sequenceo f exon 8 from 220 unrelatedi ndividuals showing transferrin phenotypes associated with the three most common Tf C alleles, Tf Cl, Tf C2 and Tf C3, and from 5 individuals showing abnormal transferrin phenotypes in the first study, were amplified by polymerase chain reaction. Amplified products were digested with the restriction endonuclease, Fok I which has a single recognition site in exon 8 containing the proposed wild-type guanine at base 1086, or with Bsm I which also shows a single recognition site containing the proposed adenine nucleotide. The study failed to detect the presence of the proposed transferrin variant, confirming that the wild-type guanine was present in all 225 individuals.
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Rohde, Kerstin, Martin Federbusch, Annette Horstmann, Maria Keller, Arno Villringer, Michael Stumvoll, Anke Tönjes, Peter Kovacs, and Yvonne Böttcher. "Genetic variants in AKR1B10 associate with human eating behavior." Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-169923.

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Background: The human Aldoketoreductase 1B10 gene (AKR1B10) encodes one of the enzymes belonging to the family of aldoketoreductases and may be involved in detoxification of nutrients during digestion. Further, AKR1B10 mRNA (messenger ribonucleic acid) expression was diminished in brain regions potentially involved in the regulation of eating behavior in rats which are more sensitive to cocaine and alcohol. We hypothesized that the human AKR1B10 gene may also play a role in the regulation of human eating behavior.
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Zhao, Jing. "Rare and common genetic variant associations with quantitative human phenotypes." Diss., Georgia Institute of Technology, 2015. http://hdl.handle.net/1853/53923.

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This dissertation aims at investigating the association between genotypes and phenotypes in human. Both common and rare regulatory variants have been studied. The phenotypes include disease risk, clinical traits and gene expression levels. This dissertation describes three different types of association study. The first study investigated the relationship between common variants and three sub-clinical traits as well as three complex diseases in the Center for Health Discovery and Well Being study (CHDWB). The second study is GWAS analysis of TNF-α and BMI/CRP conducted as a contribution to meta-GWAS analyses of these traits with investigators at the University of Groningen in the Netherlands, and the 1000 Genomes Consortium. The third study was the most original contribution of my thesis as it assessed the association between rare regulatory variants in promoter regions and gene expression levels. The results clearly show an enrichment of rare variants at both extremes of gene expression. This dissertation provides insight into how common and rare variants associate with broadly-defined quantitative phenotypes. The demonstration that rare regulatory variants make a substantial contribution to gene expression variation has important implications for personalized medicine as it implies that de novo and other rare alleles need to be considered as candidate effectors of rare disease risk.
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Ndungu, Anne. "Rare genetic variants and susceptibility to severe bacterial diseases." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:9c5745f9-50f9-469a-8771-2e49e75db7ac.

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Infectious diseases are a major cause of morbidity and mortality worldwide. Streptococcus pneumoniae and Neisseria meningitidis are major causes of severe bacterial disease which can manifest as invasive disease such as bacteraemia and meningitis. Exposure to these pathogens is relatively widespread, yet only a minority of individuals develop invasive disease. A host genetic component to infectious disease susceptibility has been implied from twin and adoptee studies. A role for rare large effect genetic variants in predisposition to infection has been demonstrated through the study of individuals with primary immunodeficiencies. However, a majority of these studies have been undertaken in individuals with a history of recurrent disease or in multi-case families. The relative role of rare genetic variants of moderate to large effect at the population level has not been widely explored. This thesis presents effort made using next generation sequencing methods to identify rare genetic variants that lead to increased susceptibility to bacterial disease focussing on meningococcal disease, pleural infection(empyema), pneumococcal disease and sepsis phenotypes. Using an exome sequencing approach in 13 cases with invasive meningococcal disease, a novel mutation leading to a complement deficiency and increased risk of meningococcal infection was identified and functionally validated in one individual. This mutation in the CFP gene was demonstrated as leading to impaired properdin secretion. Further analysis implicated loss of function mutations in CD4 and ZAP70 as novel loci for meningococcal disease susceptibility. A case control association analysis for sepsis susceptibility highlighted the possible role for small Rho GTPases in sepsis pathology. By aggregating all rare predicted deleterious mutations in a gene, four genes in this pathway, (ROCK2, ARHGAP18, FYN and CDC42BPG) were implicated as having an excess of rare deleterious variants in sepsis samples compared to population controls. A similar approach identified low frequency genetic variants in the CD109 gene as predisposing to empyema susceptibility in children. Finally, preliminary evidence from adult individuals with invasive pneumococcal disease points to a potential role of the RNASE7 gene in invasive pneumococcal disease susceptibility. This association was primarily due to a predicted deleterious missense mutation present in cases and absent in controls. Taken together, these results have identified a number of potential loci with rare variants associated with susceptibility to severe phenotypes of bacterial diseases.
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Alston, Jessica Shea. "Genetic and Functional Studies of Non-Coding Variants in Human Disease." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10515.

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Genome-wide association studies (GWAS) of common diseases have identified hundreds of genomic regions harboring disease-associated variants. Translating these findings into an improved understanding of human disease requires identifying the causal variants(s) and gene(s) in the implicated regions which, to date, has only been accomplished for a small number of associations. Several factors complicate the identification of mutations playing a causal role in disease. First, GWAS arrays survey only a subset of known variation. The true causal mutation may not have been directly assayed in the GWAS and may be an unknown, novel variant. Moreover, the regions identified by GWAS may contain several genes and many tightly linked variants with equivalent association signals, making it difficult to decipher causal variants from association data alone. Finally, in many cases the variants with strongest association signals map to non-coding regions that we do not yet know how to interpret and where it remains challenging to predict a variants likely phenotypic impact. Here, we present a framework for the genetic and functional study of intergenic regions identified through GWAS and describe application of this framework to chromosome 9p21: a non-coding region with associations to type 2 diabetes (T2D), myocardial infarction (MI), aneurysm, glaucoma, and multiple cancers. First, we compare methods for genetic fine-mapping of GWAS associations, including methods for creating a more comprehensive catalog of variants in implicated regions and methods for capturing these variants in case- control cohorts. Next, we describe an approach for using massively parallel reporter assays (MPRA) to systematically identify regulatory elements and variants across disease-associated regions. On chromosome 9p21, we fine-map the T2D and MI associations and identify, for each disease, a collection of common variants with equivalent association signals. Using MPRA, we identify hundreds of regulatory elements on chromosome 9p21 and multiple variants (including MI- and T2D-associated variants) with evidence for allelic effects on regulatory activity that can serve as a foundation for further study. More generally, the methods presented here have broad potential application to the many intergenic regions identified through GWAS and can help to uncover the mechanisms by which variants in these regions influence human disease.
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Zeron-Medina, Cuairan Jorge. "The identification and characterisation of germline genetic variants that affect human cancer." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:8942602e-c0f8-4793-8020-d2eadd41b252.

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Single nucleotide polymorphisms (SNPs) have great potential to serve as important biomarkers in the clinic to identify those at increased risk for developing cancer, progressing more rapidly, and not responding to therapies. However, the clinical application of cancer-associated SNPs has proven to be more complicated than expected. One of the necessary steps will certainly be the description of the molecular and cellular mechanisms behind the observed associations. The p53 tumour suppressor pathway harbours well-described SNPs that affect p53 signalling and cancer. The aim of the work presented in this thesis was to utilise this knowledge to more efficiently characterise cancer-associated SNPs. Firstly, cancer-associated SNPs in a p53 network gene, CD44, were studied. Specifically, based on CD44’s known roles in both p53-dependent and independent signalling, it was predicted that the cancer-associated SNPs could function as biomarkers for chronic lymphocytic leukaemia progression, and for the response to anti-EGFR therapy for colorectal cancer. Indeed, supportive data is presented. Next, a methodology is presented that aims to identify cancer-associated SNPs in functional p53 binding sites using genome-wide datasets. Interestingly, a SNP is identified that dramatically influences the ability of p53 to regulate transcription of the KITLG oncogene and that associates with one of the largest risks of cancer identified to date. Intriguingly, the SNP is also shown to have undergone positive selection throughout human evolution, signifying a selective advantage, but similar SNPs are demonstrated to be rare in the genome due to negative selection, indicating that polymorphisms in p53 binding sites have been primarily detrimental to humans. Lastly, and in order to begin to explore if other polymorphic transcription factor binding motifs could be found in cancer-associated SNPs, a methodology was designed to identify SNPs in E-box transcription factor binding motifs, as they are sensitive to single base pair changes and affect cancer. Taken together, the work presented in this thesis shows how the study of how SNPs associate with, and impact upon, cancer has great potential to improve both biological knowledge and clinical outcomes.
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Ludwig, Leif Si-Hun [Verfasser]. "Functional studies of genetic variants in human erythropoiesis / Leif Si-Hun Ludwig." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1133074413/34.

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Hasan, Mohammad Shabbir. "Identifying and Analyzing Indel Variants in the Human Genome Using Computational Approaches." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/90797.

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Insertion and deletion (indel), a common form of genetic variation, has been shown to cause or contribute to human genetic diseases and cancer. Despite this importance and being the second most abundant variant type in the human genome, indels have not been studied as much as the single nucleotide polymorphism (SNP). With the advance of next-generation sequencing technology, many indel calling tools have been developed. However, performance comparison of commonly used tools has shown that (1) the tools have limited power in identifying indels and there are significant number of indels undetected, and (2) there is significant disagreement among the indel sets produced by the tools. These findings indicate the necessity of improving the existing tools or developing new algorithms to achieve reliable and consistent indel calling results. Two indels are biologically equivalent if the resulting sequences are the same. Storing biologically equivalent indels as distinct entries in databases causes data redundancy and misleads downstream analysis. It is thus desirable to have a unified system for identifying and representing equivalent indels. This dissertation describes UPS-indel, a utility tool that creates a universal positioning system for indels so that equivalent indels can be uniquely determined by their coordinates in the new system. Results show that UPS-indel identifies more redundant indels than existing algorithms. While mapping short reads to the reference genome, a significant number of short reads are unmapped and excluded from downstream analyses, thereby causing information loss in the subsequent variant calling. This dissertation describes Genesis-indel, a computational pipeline that explores the unmapped reads to identify missing novel indels. Results analyzing sequence alignment of 30 breast cancer patients show that Genesis-indel identifies many novel indels that also show significant enrichment in oncogenes and tumor suppressor genes, demonstrating the importance of rescuing indels hidden in the unmapped reads in cancer and disease studies. Somatic mutations play a vital role in transforming healthy cells into cancer cells. Therefore, accurate identification of somatic mutations is essential. Many somatic mutations callers are available with different strengths and weaknesses. An ensemble approach integrating the power of the callers is warranted. This dissertation describes SomaticHunter, an ensemble of two callers, namely Platypus and VarDict. Results on synthetic tumor data show that for both SNPs and indels, SomaticHunter achieves recall comparable to the state-of-the-art somatic mutation callers and the highest precision, resulting in the highest F1 score.
Doctor of Philosophy
Insertion and deletion (indel), a common form of genetic variation in the human genome, is associated with genetic diseases and cancer. However, indels are heavily understudied due to experimental and computational challenges. This dissertation addresses the computational challenges in three aspects. First, the current approach of representing indels is ambiguous and causes significant database redundancy. A universal positioning system, UPS-indel, is proposed to represent equivalent indels unambiguously and the UPS-indel algorithm is theoretically proven to find all equivalent indels and is thus exhaustive. Second, a significant number of indels are hidden in DNA reads not mapped to the reference genome. Genesis-indel, a computational pipeline that explores the unmapped reads to identify novel indels that are initially missed, is developed. Genesis-indel has been shown to uncover indels that can be important genetic markers for breast cancer. Finally, mutations occurring in somatic cells play a vital role in transforming healthy cells into cancer cells. Therefore, accurate identification of somatic mutation is essential for a better understanding of cancer genomes. SomaticHunter, an ensemble of two sensitive variant callers, is developed. Simulated studies using whole genome and whole exome sequences have shown that SomaticHunter achieves recall comparable to state-of-the-art somatic mutation callers while delivering the highest precision and therefore resulting in the highest F1 score among all the callers compared.
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Arefayene, Million. "Identification and functional characterization of genetic variants in the human indoleamine 2, 3-dioxygenase (INDO) gene." Thesis, Connect to resource online, 2008. http://hdl.handle.net/1805/1704.

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Thesis (Ph.D.)--Indiana University, 2008.
Title from screen (viewed on June 4, 2009). Department of Pharmacology and Toxicology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): David A. Flockhart. Includes vita. Includes bibliographical references (leaves 124-139).
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Nisar, Samia. "Role of ATP2B4 and human malaria : looking for functional genetic variants associated with malaria." Thesis, Aix-Marseille, 2020. http://theses.univ-amu.fr.lama.univ-amu.fr/200911_NISAR_992dobfs271wcdsgy656twqjfn399ockic_TH.pdf.

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GWAS pour le paludisme grave identifié 30 variantes génétiques situées dans régions non codantes, avec seulement quelques associations répliquées dans des populations indépendantes. Dans cette étude, nous avons cherché à identifier les variantes génétiques potentielles situées dans ces loci et à démontrer leur activité fonctionnelle. Nous avons systématiquement étudié l'effet régulateur des SNP en déséquilibre liaison avec les tagSNPs associés au paludisme sévère dans plusieurs populations. L'annotation et priorisation ont conduit à l'identification d'une région régulatrice contenant 5 SNP ATP2B4 en déséquilibre liaison avec le tagSNP. Nous confirmé l'association de rs10900585 et trouvé des associations significatives de paludisme sévère avec nos candidats dans population sénégalaise. Nous montré que cette région avait à la fois une activité promoteur et un activateur et que l'individu et combinaison de SNP avaient un effet en utilisant des dosages de luciférase. En outre, la délétion médiée par CRISPR / Cas9 de cette région a diminué le transcrit ATP2B4 et les niveaux de protéines et a augmenté la concentration intracellulaire de Ca2+ dans les cellules K562. Ensemble, nos données montrent les variantes génétiques associées au paludisme grave modifient l'activité d'un promoteur avec une fonction d'activateur. Nous montré que cet amplificateur contrôle l'expression de l'ATP2B4 qui code l'ATPase 4 (PMCA4) transportant le calcium dans la membrane plasmique, qui est la principale pompe à calcium des globules rouges. La modification de l'activité de cet Epromoter affecte le risque de paludisme sévère probablement par l'effet de la concentration de calcium sur la parasitémie
Genome-wide association studies (GWAS) for severe malaria have identified 30 genetic variants mostly located in non-coding regions, with only few associations replicated in independent populations. In this study, we aimed at identifying potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium with the tagSNPs associated with severe malaria in several populations. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing 5 ATP2B4 SNPs in linkage disequilibrium with the tagSNP rs10900585. We confirmed the association of rs10900585 and also found significant associations of severe malaria with our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we showed that this region had both a promoter and an enhancer activity and that both individual SNPs and the combination of SNPs had an effect using luciferase reporter assays. In addition, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in K562 cell line. Taken together, our data show that severe malaria associated genetic variants alters the activity of a promoter with enhancer function. We showed that this enhancer controls the expression of ATP2B4 that encodes plasma membrane calcium-transporting ATPase 4 (PMCA4), which is the major calcium pump on red blood cells. Altering the activity of this Epromoter affects the risk of severe malaria probably through calcium concentration effect on parasitaemia
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Books on the topic "Human genetic variants"

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P, Winter William, ed. Hemoglobin variants in human populations. Boca Raton, Fla: CRC Press, 1986.

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author, Thompson Simon G., ed. Mendelian randomization: Methods for using genetic variants in causal estimation. Boca Raton: CRC Press, Taylor & Francis Group, 2015.

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K, Méhes, ed. Informative morphognetic variants in the newborn infant. Budapest: Akadémia Kiadó, 1988.

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Epigenetic Variants of the Human Skull. E. Schweizerbartsche Verlagsbuchhandlung, 1989.

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Frequencies of hemoglobin variants: Thalassemia, the glucose-6-phosphate dehydrogenase deficiency, G6PD variants, and ovalocytosis in human populations. New York: Oxford University Press, 1985.

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Burgess, Stephen, and Simon G. Thompson. Mendelian Randomization: Methods for Causal Inference Using Genetic Variants. Taylor & Francis Group, 2021.

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Burgess, Stephen, and Simon G. Thompson. Mendelian Randomization: Methods for Causal Inference Using Genetic Variants. Taylor & Francis Group, 2021.

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Mendelian Randomization: Methods for Causal Inference Using Genetic Variants. Taylor & Francis Group, 2021.

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Burgess, Stephen, and Simon G. Thompson. Mendelian Randomization: Methods for Using Genetic Variants in Causal Estimation. Taylor & Francis Group, 2015.

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Mendelian Randomization: Methods for Using Genetic Variants in Causal Estimation. Taylor & Francis Group, 2015.

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Book chapters on the topic "Human genetic variants"

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Medway, Christopher, Anne Braae, and Kevin Morgan. "Erythropoietin-Producing Human Hepatocellular Carcinoma (EphA1)." In Genetic Variants in Alzheimer's Disease, 191–99. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-7309-1_10.

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Song, Yiqing, Cuilin Zhang, Lu Wang, Qi Dai, and Simin Liu. "Magnesium Intake, Genetic Variants, and Diabetes Risk." In Magnesium in Human Health and Disease, 103–18. Totowa, NJ: Humana Press, 2012. http://dx.doi.org/10.1007/978-1-62703-044-1_6.

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Wachter, Kenneth W. "12. Genetic Evolutionary Demography." In Human Evolutionary Demography, 293–306. Cambridge, UK: Open Book Publishers, 2024. http://dx.doi.org/10.11647/obp.0251.12.

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Since the 1990s biodemographers comparing demographic schedules across divergent species have highlighted features in common, plausibly reflecting evolutionary influences in common. Optimal life history models and stochastic vitality models garner inspiration from Darwinian theory. Models for genetic load go further, explicitly incorporating natural selection, mutation, and recombination and consequences for genomes. These models draw age-specific demographic implications from assumptions about mutation accumulation. The genetic variants posited by the theory are now coming into observation in genomic data. A search is underway for contemporary effects of genetic load on measures of health, aging, and survival. It may be possible to tell how far an evolutionary heritage from deep in the past persists amid the altered environments of the present, shaping demographic regularities.
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Cole, Brian S., and Jason H. Moore. "EVE: Cloud-Based Annotation of Human Genetic Variants." In Applications of Evolutionary Computation, 83–95. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-55849-3_6.

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Talmud, Philippa, Alison Dunning, and Steve Humphries. "Apolipoprotein B: Genetic Variants Provide Insight into Structure and Function." In Human Apolipoprotein Mutants III, 183–94. Berlin, Heidelberg: Springer Berlin Heidelberg, 1993. http://dx.doi.org/10.1007/978-3-642-84634-2_17.

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Dumitrescu, Alexandrina L., and Junya Kobayashi. "A Gene Mutation of Major Effect on Human Disease and Its Association with Periodontitis." In Genetic Variants in Periodontal Health and Disease, 21–29. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-642-00680-7_3.

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Couvy-Duchesne, Baptiste, Simona Bottani, Etienne Camenen, Fang Fang, Mulusew Fikere, Juliana Gonzalez-Astudillo, Joshua Harvey, et al. "Main Existing Datasets for Open Brain Research on Humans." In Machine Learning for Brain Disorders, 753–804. New York, NY: Springer US, 2023. http://dx.doi.org/10.1007/978-1-0716-3195-9_24.

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AbstractRecent advances in technology have made possible to quantify fine-grained individual differences at many levels, such as genetic, genomics, organ level, behavior, and clinical. The wealth of data becoming available raises great promises for research on brain disorders as well as normal brain function, to name a few, systematic and agnostic study of disease risk factors (e.g., genetic variants, brain regions), the use of natural experiments (e.g., evaluate the effect of a genetic variant in a human population), and unveiling disease mechanisms across several biological levels (e.g., genetics, cellular gene expression, organ structure and function). However, this data revolution raises many challenges such as data sharing and management, the need for novel analysis methods and software, storage, and computing.Here, we sought to provide an overview of some of the main existing human datasets, all accessible to researchers. Our list is far from being exhaustive, and our objective is to publicize data sharing initiatives and help researchers find new data sources.
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Naushad, S. M., P. Dorababu, and R. Digumarti. "17. Genetic variants of folate metabolic pathways in hematological toxicity of leukemia patients." In Human Health Handbooks, 291–302. The Netherlands: Wageningen Academic Publishers, 2016. http://dx.doi.org/10.3920/978-90-8686-822-3_17.

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Kutzera, Joachim, and Patrick May. "Variant-DB: A Tool for Efficiently Exploring Millions of Human Genetic Variants and Their Annotations." In Lecture Notes in Computer Science, 22–28. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-69751-2_3.

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Parker, John C., and Lee R. Berkowitz. "Genetic Variants Affecting the Structure and Function of the Human Red Cell Membrane." In Clinical Disorders of Membrane Transport Processes, 19–48. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-1286-4_2.

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Conference papers on the topic "Human genetic variants"

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Sharma, S., C. Liu, A. T. Kho, R. Gaedigk, C. A. Vyhlidal, K. G. Tantisira, K. Kechris, and S. T. Weiss. "The Impact of Regulatory Genetic Variants on the Developing Human Lung." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a6086.

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Soares-Souza, Giordano B., Guilherme P. G. Kingma, Eduardo Tarazona-Santos, and Maíra R. Rodrigues. "An Agent-Based Enrichment System for Genetic Diversity Analyses." In Workshop-Escola de Sistemas de Agentes, seus Ambientes e Aplicações, 301–4. Sociedade Brasileira de Computação, 2012. https://doi.org/10.5753/wesaac.2012.33159.

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Different evolutionary forces produce genetic variants among individuals and populations. One of the most frequently studied variants is the Single Nucleotide Polymorphism (SNP). In some cases, population-specific genetic variants might be associated to diseases, resulting in a difference in the frequency of a disease among human populations. To achieve relevant genetic and biomedical knowledge, these variants need to be associated with other types of biological data, such as biochemical pathways, pharmacogenetics, and genome-wide associations. However, these data are fragmented in different databases. Therefore, it becomes necessary to develop tools to integrate distinct sources of biological data in order to enrich genetic diversity analyses. In this context, we propose an Agent-based enrichment system to integrate different sources of biologically relevant data in order to improve the genetic diversity analysis of native and Latin-American populations in particular.
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Huang, Kuan-lin, Jaiyin Wang, Song Cao, Mingchao Xie, Reyka Jayasinghe, Jie Ning, Michael McLellan, et al. "Abstract 1939: Discovery and proteogenomic investigation of genetic variants in human cancers." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1939.

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Fonseca, Alulin Tácio Quadros Santos Monteiro, Clara Gontijo Camelo, André Macedo Serafim da Silva, Cristiane Araújo Martins Moreno, and Edmar Zanoteli. "Genetic and clinical features of congenital titinopathy: a singlecenter cohort." In XIV Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2023. http://dx.doi.org/10.5327/1516-3180.141s1.425.

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Introduction: TTN has the longest coding sequence of human genes and encodes titin, a huge protein that serves as the scaffold for sarcomere assembly. Titinopathy encompasses a complex spectrum of phenotypes with involvement of skeletal and cardiac muscles, with recessive and dominant autosomal inheritance. Objectives: In this work we present the clinical and genetic data of seven patients with autosomal recessive TTN-related congenital myopathy, aged between 9 months and 38 years (mean age 14.73 years). Methods: Clinical, muscle histology and genetic data are presented. TTN gene were analyzed by next-generation sequencing (NGS). Results: Thirteen different variants were found, all classified as null variants (nonsense, frameshift or canonical splice site). All variants were presumably compound heterozygous. Only one variant was recurrent (c.44815+1G>A. All patients had a history of neonatal hypotonia. The latest age for gait acquisition was 7 years old, and a 19-year-old patient never acquired the gait. Joint hypermobility was prominent in two patients. No patient had ophthalmoparesis. Baseline CK ranged from 75 to 4619 U/L. Minicores and mild dystrophic changes were the most prominent findings on muscle biopsies. Conclusion: Congenital muscle titinopathy commonly presents with null biallelic variants. Patients who present with distal hyperelasticity, normal or slightly increased CK, and dystrophic findings on muscle biopsy may have an initial etiologic suspicion of COL6-related myopathy, a more common group of skeletal muscle disorders and important differential diagnosis of TTN myopathy.
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Wierzbicki, Andrzej J., Araba A. Adjei, Nuttapong Ngamphaiboon, Thanyanan Reungwetwattana, Andrei V. Gudkov, and Alex A. Adjei. "Abstract 5492: Functional characterization of human toll-like receptor 5 (TLR5) genetic variants." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5492.

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Alqallaf, Abdullah K., Ahmed H. Tewfik, Paula Krakowiak, Flora Tassone, Ryan Davis, Robin Hansen, Irva Hertz-Picciotto, Isaac Pessah, Jeff Gregg, and Scott B. Selleck. "Identifying patterns of copy number variants in case-control studies of human genetic disorders." In 2009 IEEE International Workshop on Genomic Signal Processing and Statistics (GENSIPS). IEEE, 2009. http://dx.doi.org/10.1109/gensips.2009.5174366.

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Ni, L. "Role of Human SP-D Genetic Variants in the Pathogenesis of Chronic Lung Injury." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a5372.

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Younes, Nadin, Atiyeh Abdallah, and Marawan Abu madi. "A Whole-Genome Sequencing Association Study of Low Bone Mineral Density Identifies New Susceptibility Loci in the Phase I Qatar Biobank Cohort." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0115.

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Introduction: Bone density disorders are characterized by a reduction in bone mass density and strength, which lead to an increase in the susceptibility to sudden and unexpected fractures. Despite the serious consequences of low bone mineral density (BMD) and its significant impact on human health, most affected individuals may not know that they have the disease because it is asymptomatic. Therefore, understanding the genetic basis of low BMD and osteoporosis is essential to fully elucidate its pathobiology and devise preventative or therapeutic approaches. Materials and Methods: we sequenced the whole genomes of 3000 individuals from the Qatar Biobank and conducted genome-wide association analyses to identify genetic risk factors associated with low BMD in the Qatari population. Results: Fifteen variants were significantly associated with total body BMD (p < 5 × 10-8). Of these, five variants had previously been reported by and were directionally consistent with previous genome-wide association study data. Ten variants were new: six intronic variants located at six gene loci (MALAT1/TALAM1, FASLG, LSAMP, SAG, FAM189A2, and LOC101928063) and four intergenic variants. Conclusion: This first such study in Qatar provides a new insight into the genetic architecture of low BMD in the Qatari population. Nevertheless, more studies are needed to validate these findings and to elucidate the functional effects of these variants on low BMD and bone fracture susceptibility.
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Wilhelm, S., and A. Henschen. "ON THE IDENTIFICATION OF POLYMORPHIC SITES IN HUMAN FIBRINOGEN PEPTIDE CHAINS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643327.

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Human fibrinogen has repeatedly been shown to occur in a great number of different molecular forms. Some types of heterogeneity are evident already from variations in solubility properties and in ion-exchange-chromatographic as well as gel-electrophoretic behaviour of the total molecule and of its peptide chain components. The reason for these variations are partly known.Thus, degradation of the C-terminal parts and phosphorylation of two serine residues gives rise to heterogeneity in the Aα-chain. Differences in the sialylation of the carbohydrate side chain causes heterogeneity both in the Bβ- and the γ-chain. Differences in chain length at the C-terminus of the γ-chain are responsible for additional variation. All these variants are expected to exist in each human being. An other category of human fibrinogen variants may be due to genetic polymorphism within the population, i.e. the presence of inherited, common, normal variants. Seven sites of microheterogeneity have so far been tentatively identified, mainly by disagreements between protein and DNA sequence analyses. Three of the sites are located in the Aα-chain (positions 47, 296 and 312), three in the Bβ-chain (positions 162, 296 and 44-8) and one in the γ-chain (position 88). The aim of the present study was to identify these sites on the proteinchemical level in pooled plasma as well as in plasma from single individuals, especially various members of the same family. For this purpose suitable fibrinogen fragments containing the tentatively microheterogeneous sites were isolated after cleavage of fibrinogen with cyanogen bromide, trypsin and/or chymotrypsin by repeated fractionations by means of conventional and reversed-phase high-performance liquid chromatography and counter-current distribution. The components were characterized by N-terminal sequence and amino acid composition. Polymorphism in human fibrinogen has previously only once been identified by restriction fragment length analysis in a non-transcribed region of the Aα-chain locus but never in the transcribed regions, i.e. the peptide chains.The present investigation will allow the estimation of the number of peptide chain haplotypes and their possible correlation to other genetic variants of fibrinogen.
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Kobayashi, Nobumitsu, Yunden Droma, Masao Ota, and Masayuki Hanaoka. "Human exome analysis of candidate genetic variants for susceptibility to high-altitude pulmonary edema in Japanese." In ERS International Congress 2020 abstracts. European Respiratory Society, 2020. http://dx.doi.org/10.1183/13993003.congress-2020.1126.

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Reports on the topic "Human genetic variants"

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Hansen, Peter J., Zvi Roth, and Jeremy J. Block. Improving oocyte competence in dairy cows exposed to heat stress. United States Department of Agriculture, January 2014. http://dx.doi.org/10.32747/2014.7598163.bard.

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Original Objectives. The overall goal is to develop methods to increase pregnancy rate in lactating dairy cows exposed to heat stress through methods that minimize damage to the oocyte and embryo caused by heat stress. Objectives were as follows: (1) examine the protective effects of melatonin on developmental competence of oocytes exposed to elevated temperature in vitro; (2) test whether melatonin feeding can improve developmental competence of oocytes in vivo and, if so, whether effects are limited to the summer or also occur in the absence of heat stress; and (3) evaluate the effectiveness of improving fertility by facilitating follicular turnover in the summer and winter. Revised Objectives. (1) Examine protective effects of melatonin and follicular fluid on developmental competence of oocytes exposed to elevated temperature in vitro; (2) examine the protective effects of melatonin on developmental competence of embryos exposed to elevated temperature in vitro; (3) evaluate effectiveness of improving fertility by administering human chorionicgonadotropin (hCG) to increase circulating concentrations of progesterone and evaluate whether response to hCG depends upon genotype for four mutations reported to be related to cow fertility; and (4) identify genes with allelic variants that increase resistance of embryos to heat shock. Background. The overall hypothesis is that pregnancy success is reduced by heat stress because of damage to the oocyte and cleavage-stage embryo mediated by reactive oxygen species (ROS), and that fertility can be improved by provision of antioxidants or by removing follicles containing oocytes damaged by heat stress. During the study, additional evidence from the literature indicated the potential importance of treatment with chorionicgonadotropin to increase fertility of heat- stressed cows and results from other studies in our laboratories implicated genotype as an important determinant of cow fertility. Thus, the project was expanded to evaluate hCG treatment and to identify whether fertility response to hCG depended upon single nucleotide polymorphisms (SNP) in genes implicated as important for cow fertility. We also evaluated whether a SNP in a gene important for cellular resistance to heat stress (HSPA1L, a member of the heat shock protein 70 family) is important for embryonic resistance to elevated temperature. Major conclusions, solutions & achievements. Results confirmed that elevated temperature increases ROS production by the oocyte and embryo and that melatonin decreases ROS. Melatonin reduced, but did not completely block, damaging effects of heat shock on the oocyte and had no effect on development of the embryo. Melatonin was protective to the oocyte at 0.1-1 μM, a concentration too high to be achieved in cows. It was concluded that melatonin is unlikely to be a useful molecule for increasing fertility of heat-stressed cows. Treatment with hCG at day 5 after breeding increased first-service pregnancy rate for primiparous cows but not for multiparous cows. Thus, hCG could be useful for increasing fertility in first-parity cows. The effectiveness of hCG depended upon genotype for a SNP in COQ9, a gene encoding for a mitochondrial-function protein. This result points the way to future efforts to use genetic information to identify populations of cows for which hormone treatments will be effective or ineffective. The SNP in HSPA1L was related to embryonic survival after heat shock. Perhaps, genetic selection for mutations that increase cellular resistance to heat shock could be employed to reduce effects of heat stress on fertility. Implications, both scientific and agricultural. This project has resulted in abandonment of one possible approach to improve fertility of the heat-stressed cow (melatonin therapy) while also leading to a method for improving fertility of primiparous cows exposed to heat stress (hCG treatment) that can be implemented on farms today. Genetic studies have pointed the way to using genetic information to 1) tailor hormonal treatments to cow populations likely to respond favorably and 2) select animals whose embryos have superior resistance to elevated body temperatures.
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