Mother’s curse neutralizes natural selection against a human genetic disease over three centuries

Abstract

According to evolutionary theory, mitochondria could be poisoned gifts that mothers transmit to their sons. This is because mutations harmful to males are expected to accumulate in the mitochondrial genome, the so-called 'mother's curse'. However, the contribution of the mother's curse to the mutation load in nature remains largely unknown and hard to predict, because compensatory mechanisms could impede the spread of deleterious mitochondria. Here we provide evidence for the mother's curse in action over 290 years in a human population. We studied a mutation causing Leber's hereditary optical neuropathy, a disease with male-biased prevalence and which has long been suspected to be maintained in populations by the mother's curse. Male carriers showed a low fitness relative to non-carriers and to females, mostly explained by their high rate of infant mortality. Despite poor male fitness, selection analysis predicted a slight (albeit non-significant) increase in frequency, which sharply contrasts with the 35.5% per-generation decrease predicted if mitochondrial DNA transmission had been through males instead of females. Our results are therefore even suggestive of positive selection through the female line that may exacerbate effects of the mother's curse. This study supports a contribution of the mother's curse to the reduction of male lifespan, uncovering a large fitness effect associated with a single mitochondrial variant.

Maternal inheritance of mitochondria: implications for male fertility?

“…We believe the coming years will provide crucial resolution of these questions, inspired by emerging research that suggests a role for the Mother's Curse hypothesis in human reproductive biology (Dowling 2014, Milot et al 2017.…”

“…Thus, this is the candidate SNP causing the sterility, although it is possible that other currently cryptic variation in the D-loop is driving the effects (Wolff et al 2017). These subfertility effects associated with this haplotype have been confirmed across all nuclear genetic and environmental contexts in which males harbouring this haplotype have been tested (Clancy et al 2008, Yee et al 2013, Dowling et al 2015, Wolff et al 2016a,b, 2017. Indeed, in one nuclear background in which the haplotype has been tested, the spermatids of these males fail to individualise and degrade within the testes (Clancy et al 2011), leaving the males completely infertile.…”

“…All of the fruit fly examples come from studies of D. melanogaster, and many of these have utilised the same panel of naturally occurring mtDNA haplotypes (Clancy et al 2008, 2011, Innocenti et al 2011, Yee et al 2013, Dowling et al 2015, Wolff et al 2016a,b, 2017, which were originally sourced from different global localities and which exhibit generally low levels of sequence divergence (~0.4%); a level of divergence paralleling that seen between major human mtDNA haplogroups (Morrow et al 2015). Replicate genetic strains have been created for each of these haplotypes, with each haplotype placed alongside a standardised isogenic background (i.e.…”

Allele frequency dynamics in a pedigreed natural population

“…Also, empirical pedigree calculations have long been used to understand genetic models of human diseases (13) and are increasingly used in natural populations to understand the genetic basis of quantitative trait variation, fitness consequences of inbreeding, and much more (14). To date, empirical pedigrees and gene dropping approaches have been rarely used to study the temporal spread and loss of individual alleles (15)(16)(17)(18).Here, we combine genomic data with a known population pedigree to describe and predict allele frequency change at many loci in an exhaustively sampled free-living population of Florida Scrub-Jays (Aphelocoma coerulescens) at Archbold Biological Station. Intensive study since 1969 has resulted in lifetime fitness measures for thousands of individuals on an extensive pedigree.…”

“…Also, empirical pedigree calculations have long been used to understand genetic models of human diseases (13) and are increasingly used in natural populations to understand the genetic basis of quantitative trait variation, fitness consequences of inbreeding, and much more (14). To date, empirical pedigrees and gene dropping approaches have been rarely used to study the temporal spread and loss of individual alleles (15)(16)(17)(18).…”