The Effect of Genomic Inversions on Estimation of Population Genetic Parameters from SNP Data

Abstract

In recent years it has emerged that structural variants have a substantial impact on genomic variation. Inversion polymorphisms represent a significant class of structural variant, and despite the challenges in their detection, data on inversions in the human genome are increasing rapidly. Statistical methods for inferring parameters such as the recombination rate and the selection coefficient have generally been developed without accounting for the presence of inversions. Here we exploit new software for simulating inversions in population genetic data, invertFREGENE, to assess the potential impact of inversions on such methods. Using data simulated by invertFREGENE, as well as real data from several sources, we test whether large inversions have a disruptive effect on widely applied population genetics methods for inferring recombination rates, for detecting selection, and for controlling for population structure in genome-wide association studies (GWAS). We find that recombination rates estimated by LDhat are biased downward at inversion loci relative to the true contemporary recombination rates at the loci but that recombination hotspots are not falsely inferred at inversion breakpoints as may have been expected. We find that the integrated haplotype score (iHS) method for detecting selection appears robust to the presence of inversions. Finally, we observe a strong bias in the genome-wide results of principal components analysis (PCA), used to control for population structure in GWAS, in the presence of even a single large inversion, confirming the necessity to thin SNPs by linkage disequilibrium at large physical distances to obtain unbiased results. INVERSION polymorphisms are a copy-neutral form of structural variant, which although largely uncataloged in human populations, are likely a common feature in the human genome (Kidd et al. 2008). The study of inversions in human populations is in its infancy but early indications suggest that their influence on genetic variation (Stefansson et al. 2005) and phenotypic traits (Tantisira et al. 2008) may be significant. One of the first large inversions (1.1 Mb) to have been discovered in the human genome is located at the MAPT locus on chromosome 17 (Boettger et al. 2012;Steinberg et al. 2012). The inverted sequence was found to be associated with elevated fertility in women and an increased recombination rate genome-wide (Stefansson et al. 2005). Another study found that three of five detected inversions were located at sites of recurrent microdeletion associated with human disease (Kidd et al. 2008), adding to several studies linking inversions with susceptibility to disease (Lakich et al. 1993;Osborne et al. 2001;Koolen et al. 2006;Tantisira et al. 2008;Antonacci et al. 2009). Supporting Information, Figure S1 shows the distribution of known human inversions according to the TCAG database.To complement the investigation of the biological impact of inversions, it is important to establish their effect on methods that exploit genetic variation data to...

Comparative Population Genomics Analysis of the Mammalian Fungal Pathogen Pneumocystis

“…These traits are considered strong suppressors of recombination (34). Estimates of population structure can be biased by the presence of large inversions as these genomic regions are inherited without recombination (35). To explore the population structure, we selected sets of SNPs in P. jirovecii (n ϭ 3,515), P. carinii (n ϭ 6,696), and P. murina (n ϭ 29,692) that were close to linkage equilibrium (pairwise r 2 , Ͻ0.5) and were randomly distributed across the genomes (Monte Carlo permutation test P ϭ 0.0019; Fig.…”

Population Genomic Analysis Reveals Differential Evolutionary Histories and Patterns of Diversity across Subgenomes and Subpopulations of Brassica napus L.

“…For example, alleles located within inverted regions cannot be freely exchanged between cultivars carrying opposite orientations. In addition, SNPs located in large inversions disproportionately contribute to PCA loadings and may bias correction for population structure in genome-wide association studies ( Seich al Basatena et al, 2013 ). More generally, further improving the characterization of the genetic diversity is crucial to achieve an effective management of the gene pool while meeting breeding challenges such as the development of improved cultivars for human consumption, animal feed or feedstocks for biofuel production.…”

Evidence for Stabilizing Selection on Codon Usage in Chromosomal Rearrangements ofDrosophila pseudoobscura

“…It should be noted that in computer simulations of human sequences, a statistical method similar to LDhelmet, LDhat ( McVean et al 2004 ), has been demonstrated to produce a slight downward bias in the recombination rate estimates when inversions are present ( Basatena et al 2013 ). However, these simulations were performed using just one gene arrangement and detectable differences between the predicted and actual recombination rate only occurred when the inverted chromosome was present at high frequencies (>80%).…”