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Correlation of the 4977 bp mitochondrial DNA deletion with human sperm dysfunction.

ABSTRACT: BACKGROUND: Several studies have examined the association between mitochondrial DNA (mtDNA) deletions, in particular the "common" 4977-bp deletion, and human sperm dysfunction, but have produced contradictory results. FINDINGS: Here we show that PCR slippage and primer miss-match to nuclear DNA may lead to overestimates in the frequency of deletions. Our investigation resolves this issue and gives strong negative correlation between the proportion of the "common" deletion and sperm motility. Furthermore, for the first time, we present data which reinforce the hypothesis for a negative correlation between the mtDNA "common" deletion and fertilization efficiency of spermatozoa. CONCLUSION: The present analysis resolves several literature inconsistencies and opens the way for diagnostic use of the "common" deletion as a molecular indicator of sperm fertility potential.

SUBMITTER: Ieremiadou F

PROVIDER: S-EPMC2642850 | biostudies-other | 2009

REPOSITORIES: biostudies-other

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Correlation of the 4977 bp mitochondrial DNA deletion with human sperm dysfunction.

Ieremiadou Fotini F Rodakis George C GC

BMC research notes 20090204

<h4>Background</h4>Several studies have examined the association between mitochondrial DNA (mtDNA) deletions, in particular the "common" 4977-bp deletion, and human sperm dysfunction, but have produced contradictory results.<h4>Findings</h4>Here we show that PCR slippage and primer miss-match to nuclear DNA may lead to overestimates in the frequency of deletions. Our investigation resolves this issue and gives strong negative correlation between the proportion of the "common" deletion and sperm ...[more]

PMID: 19192313

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Project description:BackgroundSemen quality and insemination success are monitored in artificial insemination bulls to ensure high male fertility rates. Only ejaculates that fulfill minimum quality requirements are processed and eventually used for artificial inseminations. We examined 70,990 ejaculates from 1343 Brown Swiss bulls to identify bulls from which all ejaculates were rejected due to low semen quality. This procedure identified a bull that produced 12 ejaculates with an aberrantly small number of sperm (0.2 ± 0.2 × 109 sperm per mL) which were mostly immotile due to multiple morphological abnormalities.ResultsThe genome of this bull was sequenced at a 12× coverage to investigate a possible genetic cause. Comparing the sequence variant genotypes of this bull with those from 397 fertile bulls revealed a 1-bp deletion in the coding sequence of the QRICH2 gene which encodes the glutamine rich 2 protein, as a compelling candidate causal variant. This 1-bp deletion causes a frameshift in translation and a premature termination codon (ENSBTAP00000018337.1:p.Cys1644AlafsTer52). The analysis of testis transcriptomes from 76 bulls showed that the transcript with the premature termination codon is subject to nonsense-mediated mRNA decay. The 1-bp deletion resides in a 675-kb haplotype that includes 181 single nucleotide polymorphisms (SNPs) from the Illumina BovineHD Bead chip. This haplotype segregates at a frequency of 5% in the Brown Swiss cattle population. Our analysis also identified another bull that carried the 1-bp deletion in the homozygous state. Semen analyses from the second bull confirmed low sperm concentration and immotile sperm with multiple morphological abnormalities that primarily affect the sperm flagellum and, to a lesser extent, the sperm head.ConclusionsA recessive loss-of-function allele of the bovine QRICH2 gene likely causes low sperm concentration and immotile sperm with multiple morphological abnormalities. Routine sperm analyses unambiguously identify homozygous bulls for this allele. A direct gene test can be implemented to monitor the frequency of the undesired allele in cattle populations.

Project description:Study questionAre sperm mitochondrial DNA copy number (mtDNAcn) and deletion rate (mtDNAdel) associated with odds of fertilization and high embryo quality at Days 3 and 5?Summary answerHigher sperm mtDNAcn and mtDNAdel were associated with lower odds of high quality Day 3 embryos and transfer quality Day 5 embryos, both of which were primarily driven by lowered odds of fertilization.What is known alreadySperm mtDNAcn and mtDNAdel have been previously associated with poor semen parameters and clinical male infertility. One prior study has shown that mtDNAdel is associated with lower fertilization rates. However, it is unknown whether these characteristics are linked with ART outcomes.Study design, size, durationThis prospective observational study included 119 sperm samples collected from men undergoing ART in Western Massachusetts. ART outcomes were observed through to Day 5 post-insemination.Participants/materials, settings, methodsAs part of the Sperm Environmental Epigenetics and Development Study (SEEDS), 119 sperm samples were collected from men undergoing ART in Western Massachusetts. Sperm mtDNAcn and mtDNAdel were measured via triplex probe-based qPCR. Fertilization, Day 3 embryo quality and Day 5 embryo quality measures were fitted with mtDNAcn and mtDNAdel using generalized estimating equations.Main results and the role of chanceAfter adjusting for male age and measurement batches, higher sperm mtDNAcn and mtDNAdel were associated with lower odds of fertilization (P = 0.01 and P < 0.01), high quality Day 3 embryos (P = 0.02 for both) and transfer quality Day 5 embryos (P = 0.01 and P = 0.09). However, the associations of mtDNAcn and mtDNAdel with Day 3 high quality status and Day 5 transfer quality status were attenuated in models restricted to fertilized oocytes. Sperm mtDNAcn and mtDNAdel remained statistically significant in models adjusted for both male age and semen parameters, although models including both mtDNA markers generally favoured mtDNAdel.Limitations, reasons for cautionOur sample only included oocytes and embryos from 119 couples and thus large diverse cohorts are necessary to confirm the association of sperm mtDNA biomarkers with embryo development.Wider implications of the findingsTo our knowledge, our study is the first to assess the associations of sperm mtDNAcn and mtDNAdel with fertilization and embryo quality. The biological mechanism(s) underlying these associations are unknown. Multivariable models suggest that sperm mtDNAcn and mtDNAdel provide discrimination independent of age and semen parameters; therefore, future investigation of the utility of sperm mtDNA as a biomarker for ART outcomes is warranted.Study funding/competing interest(s)This work was supported by Grant (K22-ES023085) from the National Institute of Environmental Health Sciences. The authors declare no competing interests.Trial registration numberN/A.

Dataset Information

Correlation of the 4977 bp mitochondrial DNA deletion with human sperm dysfunction.

Publications

Correlation of the 4977 bp mitochondrial DNA deletion with human sperm dysfunction.

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