Relaxed Selection During a Recent Human Expansion.

Humans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that: (i) both new and low-frequency variants are significantly more deleterious in front than in core individuals, (ii) equally deleterious mutations are at higher frequencies in front individuals, and (iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past six to nine generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection mainly due to higher rates of genetic drift on the wave front. Demographic inference and modeling of the evolution of rare variants suggest lower effective size on the front, and lead to an estimation of selection coefficients that increase with conservation scores. Even though range expansions have had a relatively limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions of Quebec.

Recombination affects accumulation of damaging and disease-associated mutations in human populations.

Many decades of theory have demonstrated that, in non-recombining systems, slightly deleterious mutations accumulate non-reversibly, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion; however, it is not clear the extent to which damaging mutations accumulate along chromosomes with highly variable rates of crossing over. Using high-coverage sequencing data from over 1,400 individuals in the 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the distribution of putatively deleterious variants across the entire human genome. Exons in regions of low recombination are significantly enriched for deleterious and disease-associated variants, a signature varying in strength across worldwide human populations with different demographic histories. Regions with low recombination rates are enriched for highly conserved genes with essential cellular functions and show an excess of mutations with demonstrated effects on health, a phenomenon likely affecting disease susceptibility in humans.

High-resolution genomic analysis of human mitochondrial RNA sequence variation.

Mutations in the mitochondrial genome are associated with multiple diseases and biological processes; however, little is known about the extent of sequence variation in the mitochondrial transcriptome. By ultra-deeply sequencing mitochondrial RNA (>6000×) from the whole blood of ~1000 individuals from the CARTaGENE project, we identified remarkable levels of sequence variation within and across individuals, as well as sites that show consistent patterns of posttranscriptional modification. Using a genome-wide association study, we find that posttranscriptional modification of functionally important sites in mitochondrial transfer RNAs (tRNAs) is under strong genetic control, largely driven by a missense mutation in MRPP3 that explains ~22% of the variance. These results reveal a major nuclear genetic determinant of posttranscriptional modification in mitochondria and suggest that tRNA posttranscriptional modification may affect cellular energy production.