Phylogenetic and population-based approaches to mitogenome variation do not support association with male infertility

J Hum Genet. 2017 Mar;62(3):361-371. doi: 10.1038/jhg.2016.130. Epub 2016 Dec 1.


Infertility has a complex multifactorial etiology and a high prevalence worldwide. Several studies have pointed to variation in the mitochondrial DNA (mtDNA) molecule as a factor responsible for the different disease phenotypes related to infertility. We analyzed 53 mitogenomes of infertile males from Galicia (northwest Spain), and these haplotypes were meta-analyzed phylogenetically with 43 previously reported from Portugal. Taking advantage of the large amount of information available, we additionally carried out association tests between patient mtDNA single-nucleotide polymorphisms (mtSNPs) and haplogroups against Iberian matched controls retrieved from The 1000 Genomes Project and the literature. Phylogenetic and association analyses did not reveal evidence of association between mtSNPs/haplogroups and infertility. Ratios and patterns in patients of nonsynonymous/synonymous changes, and variation at homoplasmic, heteroplasmic and private variants, fall within expected values for healthy individuals. Moreover, the haplogroup background of patients was variable and fits well with patterns typically observed in healthy western Europeans. We did not find evidence of association of mtSNPs or haplogroups pointing to a role for mtDNA in male infertility. A thorough review of the literature on mtDNA variation and infertility revealed contradictory findings and methodological and theoretical problems that overall undermine previous positive findings.

MeSH terms

  • DNA, Mitochondrial / genetics*
  • Haplotypes*
  • Humans
  • Infertility, Male / epidemiology
  • Infertility, Male / genetics*
  • Infertility, Male / physiopathology
  • Male
  • Mutation
  • Phylogeny*
  • Phylogeography
  • Polymorphism, Single Nucleotide*
  • Portugal / epidemiology
  • Semen Analysis
  • Spain / epidemiology
  • Sperm Count
  • Spermatozoa / metabolism*
  • Spermatozoa / pathology


  • DNA, Mitochondrial