From high masked to high realized genetic load in inbred Scandinavian wolves

When new mutations arise at functional sites they are more likely to impair than improve fitness. If not removed by purifying selection, such deleterious mutations will generate a genetic load that can have negative fitness effects in small populations and increase the risk of extinction. This is relevant for the highly inbred Scandinavian wolf (Canis lupus) population, founded by only three wolves in the 1980s and suffering from inbreeding depression. We used functional annotation and evolutionary conservation scores to study deleterious variation in a total of 209 genomes from both the Scandinavian and neighboring wolf populations in northern Europe. The masked load (deleterious mutations in heterozygote state) was highest in Russia and Finland with deleterious alleles segregating at lower frequency than neutral variation. Genetic drift in the Scandinavian population led to the loss of ancestral alleles, fixation of deleterious variants and a significant increase in the per-individual realized load (deleterious mutations in homozygote state; an increase by 45% in protein-coding genes) over five generations of inbreeding. Arrival of immigrants gave a temporary genetic rescue effect with ancestral alleles re-entering the population and thereby shifting deleterious alleles from homozygous into heterozygote genotypes. However, in the absence of permanent connectivity to Finnish and Russian populations, inbreeding has then again led to the exposure of deleterious mutations. These observations provide genome-wide insight into the magnitude of genetic load and genetic rescue at the molecular level, and in relation to population history. They emphasize the importance of securing gene flow in the management of endangered populations.

当新的突变出现在功能位点（functional sites）时，它们更有可能损害而非提升生物体的适合度（fitness）。若未被纯化选择（purifying selection）清除，这类有害突变会产生遗传负荷（genetic load），在小型种群中会对个体适合度造成负面影响，并提升种群灭绝风险。这与高度近交的斯堪的纳维亚狼（Canis lupus）种群密切相关——该种群于20世纪80年代仅由3只狼奠基建立，且饱受近交衰退（inbreeding depression）困扰。我们借助功能注释（functional annotation）与进化保守性评分（evolutionary conservation scores），对北欧斯堪的纳维亚及邻近狼种群的共计209个基因组中的有害变异展开研究。杂合状态（heterozygote state）下的有害突变所构成的隐藏遗传负荷（masked load）在俄罗斯和芬兰种群中最高，且有害等位基因的分离频率低于中性变异。斯堪的纳维亚种群中的遗传漂变（genetic drift）导致祖先等位基因（ancestral alleles）丢失、有害变异的固定（fixation），且经过五代近交后，个体实际携带的遗传负荷——即纯合状态（homozygote state）下的有害突变——在蛋白编码基因中显著提升了45%。移民个体的迁入带来了暂时性的遗传拯救（genetic rescue）效应：祖先等位基因重新进入该种群，进而将有害等位基因从纯合基因型转变为杂合基因型。但由于与芬兰、俄罗斯种群缺乏永久的基因交流，近交再次导致有害突变的暴露。这些发现从分子层面结合种群历史，为遗传负荷与遗传拯救的程度提供了全基因组层面的见解，同时也强调了在濒危种群管理中保障基因流动的重要性。