Genomic analysis of inbreeding depression in the wild.

自达尔文以来，近亲交配的有害后果一直令科学家们着迷。一个半世纪后，我们知道近亲繁殖抑制在二倍体生物体中普遍存在，其对广泛的特征、个体适应性和种群生存能力的关键影响的证据来自动植物王国的所有地方。尽管近亲繁殖抑制具有巨大的意义，但人们对其最基本的特征知之甚少：基因组中有多少区域与近亲繁殖抑制有关？潜在的基因和等位基因是什么，它们的有害影响有多大？近亲繁殖抑郁症在几代人中被选中对抗的强度有多大？近亲交配抑郁是在生命早期还是在生命后期更强烈？这些问题只能在野生种群中解决，在那里，适合度可以在自然环境的压力下进行测量，但直到最近，我们还缺乏回答这些问题的基因组工具。在这里，我提议对野生种群中近亲繁殖衰退进行最深入的基因组研究。在世界上表型最好的自由生活研究群体之一，圣基尔达的Soay绵羊，我将使用选定家系成员的高密度SNP数据，结合全群体50k SNP芯片数据，在数千个研究个体的基因组中推测超过450,000个SNP基因型。利用这个数据集，我将量化基因组中按下降完全相同(IBD)的区域，以(1)调查大多数近亲繁殖抑制是否存在于源于最近近亲繁殖的IBD的长范围内，(2)量化种群中胚胎致命等位基因的丰度，(3)定位导致近亲繁殖抑制的整个基因组的遗传变异，并使用现有的和新的方法相结合来量化它们的影响大小，以及(4)利用全基因组测序数据跟踪大效应基因座，以便更深入地研究潜在的基因和涉及的选择模式。

The detrimental consequences of inbreeding have fascinated scientists since Darwin. One and a half centuries later, we know that inbreeding depression is ubiquitous in diploid organisms and evidence for its critical impacts on a broad range of traits, individual fitness and population viability comes from all over the animal and plant kingdoms. Despite the enormous significance of inbreeding depression, little is known about its most fundamental features: How many regions of the genome contribute to inbreeding depression? What are the underlying genes and alleles and how strong are their deleterious effects? How strongly is inbreeding depression selected against over the generations? Is inbreeding depression stronger in earlier or in later life-stages? These questions can only be addressed in wild populations, where fitness can be measured under the pressures of natural environments, but until recently we lacked the genomic tools to answer them. Here, I propose the most in-depth genomic investigation of inbreeding depression in a wild population to date. In one of the best-phenotyped free-living study populations in the world, the Soay sheep of St Kilda, I will use high density SNP data for selected pedigree members in combination with population-wide 50k SNP chip data to impute more than 450,000 SNP genotypes throughout the genomes of thousands of study individuals. Using this dataset, I will quantify regions in the genome which are identical-by-descent (IBD) to (1) investigate whether most inbreeding depression resides in long stretches of IBD derived from recent inbreeding, (2) quantify the abundance of embryonic lethal alleles in the population, (3) locate the genetic variants causing inbreeding depression across the genome and quantify their effect sizes using a combination of established and novel methods and (4) follow-up large effect loci using whole-genome-sequencing data for a deeper investigation of the underlying genes and the mode of selection involved.