Investigation of Inversion Polymorphisms in the Human Genome Using Principal Components Analysis

Abstract

Despite the significant advances made over the last few years in mapping inversions with the advent of paired-end sequencing approaches, our understanding of the prevalence and spectrum of inversions in the human genome has lagged behind other types of structural variants, mainly due to the lack of a cost-efficient method applicable to large-scale samples. We propose a novel method based on principal components analysis (PCA) to characterize inversion polymorphisms using high-density SNP genotype data. Our method applies to non-recurrent inversions for which recombination between the inverted and non-inverted segments in inversion heterozygotes is suppressed due to the loss of unbalanced gametes. Inside such an inversion region, an effect similar to population substructure is thus created: two distinct “populations” of inversion homozygotes of different orientations and their 1∶1 admixture, namely the inversion heterozygotes. This kind of substructure can be readily detected by performing PCA locally in the inversion regions. Using simulations, we demonstrated that the proposed method can be used to detect and genotype inversion polymorphisms using unphased genotype data. We applied our method to the phase III HapMap data and inferred the inversion genotypes of known inversion polymorphisms at 8p23.1 and 17q21.31. These inversion genotypes were validated by comparing with literature results and by checking Mendelian consistency using the family data whenever available. Based on the PCA-approach, we also performed a preliminary genome-wide scan for inversions using the HapMap data, which resulted in 2040 candidate inversions, 169 of which overlapped with previously reported inversions. Our method can be readily applied to the abundant SNP data, and is expected to play an important role in developing human genome maps of inversions and exploring associations between inversions and susceptibility of diseases.

Ancient DNA reveals the Arctic origin of Viking Age cod from Haithabu, Germany

“…3A). PCAs of these inversions for the four modern populations show the typical trimodal clustering of a biallelic locus with heterozygote genotypes clustering intermediate to the two divergent homozygotes (46) (Fig. S3).…”

“…Model-based clustering was performed using ADMIXTURE v1.3 (93). PCA plots for the inverted regions (LG01, 9.1-26.2 Mbp; LG02, 18.5-24 Mbp; LG07, 13.6-23 Mbp; LG12, 1.3-13.6 Mbp) were generated without LD pruning (46). Finally, the probability of obtaining the ancient individual's composite inversion genotype from the allele frequency distribution of the four modern populations was calculated by binomial sampling of genotypes and scaling these probabilities to one.…”

Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region

“…Three of these four chromosomal locations have also been associated with inversion polymorphisms representing some of the largest inversion polymorphisms in the human genome (Giglio et al 2001(Giglio et al , 2002Hurle et al 2011;Ma and Amos 2012). Analysis of primate genomes suggests that such events have occurred recurrently (i.e., the presence of both direct and inverted haplotypes in the bonobo) (Antonacci et al 2009).…”

A sex-linked supergene controls sperm morphology and swimming speed in a songbird

“…We used a principal component analysisbased approach for detecting inversions 57 . PCAs for individual chromosomes were performed using GCTA 58 , and distinct clusters were identified at several chromosomes ( Supplementary Fig.…”