Department of Genetics Evolution and Environment, University College London, London, UK.
Department of Biology, Pennsylvania State University, University Park, PA, USA.
Genome Biol Evol. 2024 Feb 1;16(2). doi: 10.1093/gbe/evae005.
The ancestral recombination graph (ARG) is a structure that represents the history of coalescent and recombination events connecting a set of sequences (Hudson RR. In: Futuyma D, Antonovics J, editors. Gene genealogies and the coalescent process. In: Oxford Surveys in Evolutionary Biology; 1991. p. 1 to 44.). The full ARG can be represented as a set of genealogical trees at every locus in the genome, annotated with recombination events that change the topology of the trees between adjacent loci and the mutations that occurred along the branches of those trees (Griffiths RC, Marjoram P. An ancestral recombination graph. In: Donnelly P, Tavare S, editors. Progress in population genetics and human evolution. Springer; 1997. p. 257 to 270.). Valuable insights can be gained into past evolutionary processes, such as demographic events or the influence of natural selection, by studying the ARG. It is regarded as the "holy grail" of population genetics (Hubisz M, Siepel A. Inference of ancestral recombination graphs using ARGweaver. In: Dutheil JY, editors. Statistical population genomics. New York, NY: Springer US; 2020. p. 231-266.) since it encodes the processes that generate all patterns of allelic and haplotypic variation from which all commonly used summary statistics in population genetic research (e.g. heterozygosity and linkage disequilibrium) can be derived. Many previous evolutionary inferences relied on summary statistics extracted from the genotype matrix. Evolutionary inferences using the ARG represent a significant advancement as the ARG is a representation of the evolutionary history of a sample that shows the past history of recombination, coalescence, and mutation events across a particular sequence. This representation in theory contains as much information, if not more, than the combination of all independent summary statistics that could be derived from the genotype matrix. Consistent with this idea, some of the first ARG-based analyses have proven to be more powerful than summary statistic-based analyses (Speidel L, Forest M, Shi S, Myers SR. A method for genome-wide genealogy estimation for thousands of samples. Nat Genet. 2019:51(9):1321 to 1329.; Stern AJ, Wilton PR, Nielsen R. An approximate full-likelihood method for inferring selection and allele frequency trajectories from DNA sequence data. PLoS Genet. 2019:15(9):e1008384.; Hubisz MJ, Williams AL, Siepel A. Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph. PLoS Genet. 2020:16(8):e1008895.; Fan C, Mancuso N, Chiang CWK. A genealogical estimate of genetic relationships. Am J Hum Genet. 2022:109(5):812-824.; Fan C, Cahoon JL, Dinh BL, Ortega-Del Vecchyo D, Huber C, Edge MD, Mancuso N, Chiang CWK. A likelihood-based framework for demographic inference from genealogical trees. bioRxiv. 2023.10.10.561787. 2023.; Hejase HA, Mo Z, Campagna L, Siepel A. A deep-learning approach for inference of selective sweeps from the ancestral recombination graph. Mol Biol Evol. 2022:39(1):msab332.; Link V, Schraiber JG, Fan C, Dinh B, Mancuso N, Chiang CWK, Edge MD. Tree-based QTL mapping with expected local genetic relatedness matrices. bioRxiv. 2023.04.07.536093. 2023.; Zhang BC, Biddanda A, Gunnarsson ÁF, Cooper F, Palamara PF. Biobank-scale inference of ancestral recombination graphs enables genealogical analysis of complex traits. Nat Genet. 2023:55(5):768-776.). As such, there has been significant interest in the field to investigate 2 main problems related to the ARG: (i) How can we estimate the ARG based on genomic data, and (ii) how can we extract information of past evolutionary processes from the ARG? In this perspective, we highlight 3 topics that pertain to these main issues: The development of computational innovations that enable the estimation of the ARG; remaining challenges in estimating the ARG; and methodological advances for deducing evolutionary forces and mechanisms using the ARG. This perspective serves to introduce the readers to the types of questions that can be explored using the ARG and to highlight some of the most pressing issues that must be addressed in order to make ARG-based inference an indispensable tool for evolutionary research.
祖先重组图(ARG)是一种表示连接一组序列的合并和重组事件历史的结构(Hudson RR. In: Futuyma D, Antonovics J, editors. Gene genealogies and the coalescent process. In: Oxford Surveys in Evolutionary Biology; 1991. p. 1 to 44.)。完整的 ARG 可以表示为基因组中每个基因座的一组系统发育树,这些树的拓扑结构由相邻基因座之间的重组事件和沿这些树分支发生的突变所改变(Griffiths RC, Marjoram P. An ancestral recombination graph. In: Donnelly P, Tavare S, editors. Progress in population genetics and human evolution. Springer; 1997. p. 257 to 270.)。通过研究 ARG,可以深入了解过去的进化过程,例如人口事件或自然选择的影响。它被认为是群体遗传学的“圣杯”(Hubisz M, Siepel A. Inference of ancestral recombination graphs using ARGweaver. In: Dutheil JY, editors. Statistical population genomics. New York, NY: Springer US; 2020. p. 231-266.),因为它编码了生成所有等位基因和单倍型变异模式的过程,而群体遗传研究中常用的所有汇总统计量都可以从这些模式中推导出来(例如杂合度和连锁不平衡)。以前的许多进化推断都依赖于从基因型矩阵中提取的汇总统计量。使用 ARG 进行进化推断是一个重大进展,因为 ARG 是样本的进化历史表示,它显示了特定序列中重组、合并和突变事件的过去历史。从理论上讲,这种表示形式包含的信息量与可以从基因型矩阵中推导出来的所有独立汇总统计量的组合一样多,如果不是更多的话。与这个想法一致的是,一些基于 ARG 的首次分析已被证明比基于汇总统计量的分析更强大(Speidel L, Forest M, Shi S, Myers SR. A method for genome-wide genealogy estimation for thousands of samples. Nat Genet. 2019:51(9):1321 to 1329.; Stern AJ, Wilton PR, Nielsen R. An approximate full-likelihood method for inferring selection and allele frequency trajectories from DNA sequence data. PLoS Genet. 2019:15(9):e1008384.; Hubisz MJ, Williams AL, Siepel A. Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph. PLoS Genet. 2020:16(8):e1008895.; Fan C, Mancuso N, Chiang CWK. A genealogical estimate of genetic relationships. Am J Hum Genet. 2022:109(5):812-824.; Fan C, Cahoon JL, Dinh BL, Ortega-Del Vecchyo D, Huber C, Edge MD, Mancuso N, Chiang CWK. A likelihood-based framework for demographic inference from genealogical trees. bioRxiv. 2023.10.10.561787. 2023.; Hejase HA, Mo Z, Campagna L, Siepel A. A deep-learning approach for inference of selective sweeps from the ancestral recombination graph. Mol Biol Evol. 2022:39(1):msab332.; Link V, Schraiber JG, Fan C, Dinh B, Mancuso N, Chiang CWK, Edge MD. Tree-based QTL mapping with expected local genetic relatedness matrices. bioRxiv. 2023.04.07.536093. 2023.; Zhang BC, Biddanda A, Gunnarsson ÁF, Cooper F, Palamara PF. Biobank-scale inference of ancestral recombination graphs enables genealogical analysis of complex traits. Nat Genet. 2023:55(5):768-776.)。因此,人们对与 ARG 相关的 2 个主要问题产生了浓厚的兴趣:(i)如何基于基因组数据估计 ARG,以及(ii)如何从 ARG 中提取过去进化过程的信息?在这篇观点文章中,我们强调了与这些主要问题相关的 3 个主题:开发能够估计 ARG 的计算创新;估计 ARG 仍然存在的挑战;以及使用 ARG 推导出进化力量和机制的方法进展。这篇观点文章旨在向读者介绍可以使用 ARG 探索的问题类型,并强调为了使基于 ARG 的推断成为不可或缺的进化研究工具,必须解决的一些最紧迫的问题。