Large-scale functional screen identifies genetic variants with splicing effects in modern and archaic humans.
Large-scale functional screen identifies genetic variants with splicing effects in modern and archaic humans.
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DOI：
10.1073/pnas.2218308120
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发表时间：
2023-05-23
影响因子：
11.1
通讯作者：
Fairbrother, William G.
中科院分区：
文献类型：
--
作者：
Rong, Stephen;Neil, Christopher R.;Welch, Anastasia;Duan, Chaorui;Maguire, Samantha;Meremikwu, Ijeoma C.;Meyerson, Malcolm;Evans, Ben J.;Fairbrother, William G.
我们的研究揭示了现代人和古代人之间前mRNA剪接的遗传差异的影响。我们使用了一个大规模的平行实验来识别962个在现代人和古代人之间存在差异的剪接变体，包括尼安德特人和丹尼索瓦人特有的潜在致病性剪接变体，以及可能解释现代人特征差异的基因渗入剪接变体。我们的研究结果表明，在现代人群中，纯化选择对剪接变异体起作用，而正选择有利于适应性渐渗中的剪接变异体。通过区分因果关联的变异，我们的研究有助于理解现存和灭绝的人类基因变异的功能后果，以及现代人类种群中基因渗入变异的功能后果。人类与后来灭绝的其他古人类共存并杂交。我们只能通过化石记录和两种情况下的基因组序列来了解这些古老的人类。在这里，我们将尼安德特人和丹尼索瓦人的序列设计成数千个人工基因，以重建这些灭绝种群的前mRNA加工模式。在这种大规模平行剪接报告基因检测（MaPSy）中检测的5，169个等位基因中，我们报告了962个外显子剪接突变，这些突变对应于现存和灭绝的人类之间外显子识别的差异。使用MaPSy剪接变体，预测剪接变体和剪接数量性状基因座，我们表明，剪接破坏变体经历了更大的净化选择在解剖学现代人类比尼安德特人。适应性基因渗入的变体富集中等效果的剪接变体，与基因渗入后选择性剪接等位基因的阳性选择一致。作为特别引人注目的例子，我们在适应性渗入的先天免疫基因TLR1处表征了独特的组织特异性选择性剪接变体，以及在编码串珠蛋白聚糖的基因HSPG2中表征了独特的尼安德特人渗入的选择性剪接变体。我们进一步确定了仅在尼安德特人和丹尼索瓦人中发现的与精子成熟和免疫相关的基因中的潜在致病性剪接变体。最后，我们发现剪接变异体可能导致现代人类总胆红素，秃顶，血红蛋白水平和肺活量的变化。我们的研究结果提供了独特的见解自然选择作用于人类进化中的剪接，并展示了功能测定如何用于识别潜在的基因调控和表型差异的候选因果变异。
Our study reveals the impact of genetic differences in pre-mRNA splicing between modern and archaic humans. We used a massively parallel experiment to identify 962 splicing variants that differ between modern and archaic humans, including potentially pathogenic splicing variants unique to Neanderthals and Denisovans, and introgressed splicing variants that may explain differences in modern human traits. Our findings indicate that purifying selection acted against splicing variants in modern human populations, whereas positive selection favored splicing variants in adaptive introgression. By distinguishing causal from linked variants, our study contributes to understanding the functional consequences of genetic variation within extant and extinct hominins and of introgressed variation in modern human populations. Humans coexisted and interbred with other hominins which later became extinct. These archaic hominins are known to us only through fossil records and for two cases, genome sequences. Here, we engineer Neanderthal and Denisovan sequences into thousands of artificial genes to reconstruct the pre-mRNA processing patterns of these extinct populations. Of the 5,169 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 962 exonic splicing mutations that correspond to differences in exon recognition between extant and extinct hominins. Using MaPSy splicing variants, predicted splicing variants, and splicing quantitative trait loci, we show that splice-disrupting variants experienced greater purifying selection in anatomically modern humans than that in Neanderthals. Adaptively introgressed variants were enriched for moderate-effect splicing variants, consistent with positive selection for alternative spliced alleles following introgression. As particularly compelling examples, we characterized a unique tissue-specific alternative splicing variant at the adaptively introgressed innate immunity gene TLR1, as well as a unique Neanderthal introgressed alternative splicing variant in the gene HSPG2 that encodes perlecan. We further identified potentially pathogenic splicing variants found only in Neanderthals and Denisovans in genes related to sperm maturation and immunity. Finally, we found splicing variants that may contribute to variation among modern humans in total bilirubin, balding, hemoglobin levels, and lung capacity. Our findings provide unique insights into natural selection acting on splicing in human evolution and demonstrate how functional assays can be used to identify candidate causal variants underlying differences in gene regulation and phenotype.
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